Basic Principles of Drug Discovery and

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 BASIC PRINCIPLES OF DRUG
DISCOVERY AND DEVELOPMENT
 BASIC PRINCIPLES OF
DRUG DISCOVERY AND
DEVELOPMENT

SECOND EDITION

BENJAMIN E. BLASS
Temple University School of Pharmacy, Department of Pharmaceutical Sciences,
Moulder Center for Drug Discovery Research, Philadelphia, PA, United States
Academic Press is an imprint of Elsevier
125 London Wall, London EC2Y 5AS, United Kingdom
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Copyright © 2021 Elsevier Inc. All rights reserved.
No part of this publication may be reproduced or transmitted in any form or by any means,
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This book and the individual contributions contained in it are protected under copyright by the
Publisher (other than as may be noted herein).
Notices
Knowledge and best practice in this field are constantly changing. As new research and experience
broaden our understanding, changes in research methods, professional practices, or medical
treatment may become necessary.
Practitioners and researchers must always rely on their own experience and knowledge in
evaluating and using any information, methods, compounds, or experiments described herein. In
using such information or methods they should be mindful of their own safety and the safety of
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 Dedication

Sir Isaac Newton, one of the greatest scientists of his time, wrote “If I
have seen further it is by standing on the shoulders of Giants.”
Although he was almost certainly referring to his scientific achieve-
ments, the underling concept of learning from our forbearer is true in
any endeavor. Indeed, this concept can be further extended to include
those who are there in the present day, supporting the activities of an
individual as he or she attempts to accomplish that which they view as
important. With this thought in mind, I have dedicated this book to the
scientists who came before me, those who mentored me, and those who
work with me on a daily basis. In addition, and perhaps more impor-
tantly, this text is dedicated to the loving and supportive family that
has helped me become the person that I am today. Special thanks are
offered to my mother, father, sister, brother, my three children, and of
course, my wife Kathleen. These are the giants on whose shoulders I
have stood upon.
 Contents

Foreword xv

1. Drug discovery and development: An overview of modern

methods and principles 1
Drug discovery and development from 20,000 Feet 11
Target selection: the first step forward 15
Hit identification: finding a starting point 19
Identify a clinical candidate: juggling the properties 25
Questions 31
References 31

2. The drug discovery process: From ancient times to the

present day 43
The age of botanicals: pre-industrial drug discovery 44
Early biotherapeutics: before the biotechnology revolution 48
Paul Ehrlich: the father of modern drug discovery 51
Milestones in drug discovery 53
Milestones in animal models: breeding a better model 54
The Wistar rat 54
Immunocompromised mice 55
Transgenic animal models 56
Knockout animal models 58
Milestones in molecular science 60
X-ray crystallography 60
Molecular modeling and computational chemistry 63
High-throughput technology: chemical synthesis and screening science 64
Milestones in biotechnology 70
Recombinant DNA and transfection technology 72
Polymerase chain reaction technology 75
DNA Sequencing and genomics 76
Proteomics 80
Monoclonal antibody and hybridoma technology 83
The rise of biologics and macromolecular therapeutics 86
Societal and governmental impacts 87
The Pure Food and Drug Act of 1906 88
The Elixir of Sulfanilamide Disaster of 1937 89
The Thalidomide story 91
Regulatory milestones 93

vii
viii CONTENTS

Durham-Humphrey Amendment of 1951 94

Kefauver-Harris Amendment of 1962 95
Hatch-Waxman Act of 1984 96
Biologics Price Competition and Innovation Act of 2009 97
Future developments in drug discovery 99
Questions 99
References 100

3. Classical targets in drug discovery 111

Protein structure 113
Enzymes 119
Inhibition of enzymes 125
G-protein-coupled receptors 130
G-protein-dependent signaling pathways 133
Cyclic adenosine monophosphate signaling 134
IP3 signaling 136
β-Arrestin pathways 138
G-protein-coupled receptor signaling pathways 140
Modulating G-protein-coupled receptor signaling 141
Ion channels 143
Gating mechanisms 149
Ligand-gated channels 149
Voltage-gated channels 152
Other gating mechanisms 155
Membrane transport proteins (transporters) 156
Nuclear receptors 164
Nuclear receptor signaling pathways 167
Modulating nuclear receptor activity 169
Biomolecular interactions: protein/protein, protein/DNA, and protein/RNA
interfaces 170
Types of “hot spots” in biomolecular interactions 172
Stabilizing biomolecular interactions 174
Questions 176
References 176

4. In vitro screening systems 185

The language of screening: basic terms 186
Concentration response curves and IC50s 187
Dissociation constants (Kd) and inhibition constants (Ki) 188
Efficacy versus binding: EC50s 190
Agonist, partial agonist, antagonist, allosteric modulators, and inverse agonists 191
Agonists and partial agonists 192
Antagonists 193
Basal activity and inverse agonist 193
Receptor reserve 193
Allosteric modulation 194
 CONTENTS ix

Streptavidin and biotin 195

Biochemical versus cellular assays 196
Assay systems and methods of detection 198
Radioligand systems 199
Scintillation proximity assay 201
Enzyme-linked immunosorbent assay 204
Fluorescence-based assay systems 206
Fluorescence polarization 207
Fluorescence resonance energy transfer 210
Time-resolved fluorescence resonance energy transfer 214
Amplified luminescent proximity homogeneous assay (AlphaScreent) 217
Fluorescent detection of calcium flux 220
Reporter gene assays 223
Chloramphenicol acetyltransferase 224
β-Lactamase reporter assays 224
Luciferase reporter assays 226
Bioluminescence resonance energy transfer assays 228
Kinetic fluorescent measurement systems 230
Label-free assay systems 231
Cellular dielectric spectroscopy 232
Optical biosensors 233
Surface plasmon resonance technology 236
Electrophysiological patch clamp 237
Thermal shift assay 240
High content screening 243
General consideration for all screening methods 245
Questions 248
References 248

5. Medicinal chemistry 257

Structure activity relationships and structure property relationships 258
The role of chirality 263
Push and pull in structure activity relationships 266
Quantitative structure activity relationships 267
The pharmacophore 272
Developing an structure activity relationship data set 276
The structure activity relationship cycle 287
Bioisosterism 288
Structure activity relationship, selectivity, and physicochemical properties 294
“Drug-like” guidelines 295
Questions 297
References 298

6. In vitro ADME and in vivo pharmacokinetics 305

Absorption 309
Solubility 310
Permeability 315
x CONTENTS

Distribution 324
Permeability 326
Transporters 328
Plasma protein binding 330
Elimination pathways 332
Metabolism 333
Excretion 345
In vitro ADME model systems 348
In Vivo pharmacokinetics 351
Volume of distribution 353
Clearance 355
Half-life 356
Bioavailability 359
Species selection 362
Questions 362
References 364

7. Animal models of disease states 371

Sources of animal models 373
Validity of animal models 376
Species selection 377
Number of animals 378
Exemplary animal models by disease category 378
Animal models in neuroscience 379
The forced swimming test: A model of depression 379
The elevated plus maze: A measure of anxiety 380
The novel object recognition test: A model of memory and cognition 381
Contextual fear conditioning model: A model of contextual learning 382
The Morris water maze: A model of spatial learning and memory 383
Animal models of neurodegeneration 384
The SOD1G93A mouse of amyotrophic lateral sclerosis (ALS) 384
The MPTP model of Parkinson’s disease 386
Animal models of cardiovascular disease 387
Models of hypertension 387
Models of hyperlipidemia and high cholesterol 389
Models of atrial fibrillation 391
Models of heart failure 393
Animal models of infectious disease 396
Murine thigh infection model 397
Murine model of systemic infection 397
Mouse model of influenza virus infection 398
Limitations of animal models of infection 399
Animal models of oncology 400
Mouse xenograft tumor model 400
Mouse allograft tumor model 401
Genetically engineered mouse models of cancer 402
 CONTENTS xi

Animal models of pain 403

The Von Frey test 404
The Ramdall-Selitto test 405
Heat based models 406
Inflammation based models 408
Surgical models 409
General consideration for pain models 409
Animal models of diabetes 409
Animal models of drug addiction 411
Conclusion 413
Questions 414
References 414

8. Safety and toxicology 421

Sources of toxicity 423
Acute versus chronic toxicity 430
Cytotoxicity 430
Carcinogenicity, genotoxicity, and mutagenicity 432
Drug drug interactions 436
Cardiovascular safety and toxicology studies 438
Central nervous system safety and toxicology studies 445
Immune system-mediated safety issues 447
Teratogenicity 450
In vivo toxicity and safety studies 451
Questions 453
References 453

9. Antibody-drug discovery 459

IgG structure and function 461
Antibody therapy drug discovery 463
Hybridoma technology 463
Antibody phage display 469
Modified monoclonal antibodies 473
General considerations 476
Conclusion 478
Questions 478
References 478

10. Basics of clinical trials 483

Before the clinic 486
Drug supply 486
Delivery methods 489
Formulation 491
Investigational new drug application 502
Phase 1 clinical trials 504
xii CONTENTS

Phase 2 clinical trials 506

Phase 3 clinical trials 510
Phase 4 clinical trials 515
Adaptive clinical trial design 516
Meta-analysis of clinical trial data 517
Questions 519
References 519

11. Translational medicine and biomarkers 523

Definition of a biomarker and their classification 526
Characteristics and impact of biomarkers 529
Biomarkers versus surrogate endpoints 531
Imaging technologies 533
The practical application of biomarkers 540
Dipeptidyl peptidase IV inhibitors (Januvia) 541
Physiological measurements as biomarkers: Orexin antagonists 543
FDG PET imaging agent 545
The neurokinin 1 receptor, depression, and PET imaging:
The Aprepitant story 546
Cancer biomarkers 548
Conclusion 553
Questions 553
References 554

12. Organizational consideration and trends in the

pharmaceutical industry 561
Organizational structures of pharmaceutical companies 562
Business divisions interactions 562
The discovery project team evolutionary cycle 563
The business climate 567
Mergers and acquisitions 567
Contract research organizations 573
Academic drug discovery 575
Funding issues 581
Conclusion 584
Questions 584
Appendix 1 585
References 591

13. Intellectual property and patents in drug discovery 595

Patentable subject matter 597
Inherent properties and patentability 601
Novelty and the prior art 603
Obviousness and the prior art 604
Inventorship 607
 CONTENTS xiii

Assignment and ownership 609

Classification of patents and patent applications 611
Impact of overlapping patents 612
Patent applications and their contents 612
Contents of a patent application 617
Conclusion 621
Questions 622
References 622

14. Case studies in drug discovery 625

Tamiflu: From mechanism of action to marketed drug 625
Histone deacylase inhibitors: Physicochemical optimization via structural change 630
HIV protease inhibitors: Chemically complex miracle drugs 632
Nitrofurantoin: A surprisingly successful drug 637
Seldanes (Terfenadine) vs Allegras (Fexofenadine): Metabolism matters: Safety 639
Claritins (Loratadine) versus Clarinexs (Desloratadine): Metabolism matters:
Pharmacokinetics 642
MPTP: Parkinson’s disease in a bottle 644
Bupropion and Methylphenidate: Improving performance via formulation
changes 647
Selective inhibition of COX-2: The impact of an inadequate written description 651
Antibiotic resistant bacteria and the development of β-lactamase inhibitors 652
Association for Molecular Pathology vs Myriad Genetics: The validity of gene
patents 655
Conclusion 658
Questions 659
References 659

Answers to questions in textbook by chapter 665

Subject Index 693

Drug Index 713
 Foreword

The last several decades have witnessed a revolution in the drug dis-
covery and development process. Medicinal chemistry and in vitro
screening that were once major bottlenecks in the process of identifying
novel therapeutics have been dramatically accelerated through the
incorporation of automation and the development of enabling technolo-
gies such as recombinant DNA and transfection technology. High-
throughput screening, parallel synthesis, and combinatorial chemistry
have facilitated the synthesis and biological evaluation of large numbers
of potentially useful compounds. These activities, in turn, have gener-
ated vast amounts of data that can be analyzed to develop structure
activity relationships and structure property relationships useful for the
optimization of lead compounds. At the same time, new techniques,
technological advances, and a greater understanding of the importance
of pharmacokinetics, animal models, and safety studies have dramati-
cally altered how new molecules are selected for clinical study. Clinical
trial design strategies, biomarkers, translational medicine, the regulatory
landscape, intellectual property rights, and the business environment
have also changed dramatically over the course of the last 40 years.
The complexities of the drug discovery and development process
cannot be overstated, nor can the wide range of expertise required for
the successful development of new, marketable therapeutics. In order to
thrive in this very changing landscape, individuals interested in a career
in the pharmaceutical industry or related fields must be more than sim-
ply experts in their chosen field of study. They must also have an
understanding of the numerous, overlapping fields of their colleagues.
Basic Principles in Drug Discovery and Development has captured the criti-
cal information on the disparate processes, technologies, and expertise
required for modern drug discovery and development and presents it
in a logical and concise manner for students, practicing scientists, and
nonscientist with an interest in the pharmaceutical industry. Dr.
Benjamin E. Blass, an experienced educator and scientist with founda-
tional knowledge in medicinal chemistry, drug design, biological tar-
gets, and over 25 years of experience in industrial and academic drug
discovery and development, provides a comprehensive account of the
many functions involved in drug discovery and development, from

xv
xvi Foreword

initial medicinal chemistry conceptualization and in vitro biological

evaluation to clinical trials and beyond.
There are many aspects of this book that will help practicing scien-
tists, graduate students, and future drug researchers to develop a strong
foundation in the concepts that govern the multidisciplinary process of
drug discovery. Through this unique text, they will acquire an under-
standing of key aspects of drug discovery and development. The organi-
zation of the subject material was chosen to allow the readers to
incrementally increase their knowledge in the wide range of disciplines
required to identify new, marketable therapeutic agents. The book is
thoroughly written and includes 14 chapters with more than 300
figures and 900 references. Throughout the text the reader will become
familiar with more than 100 drugs and clinical candidates that exem-
plify important theories and practices.
Each chapter contains examples of drugs pertaining to the material in
the chapter. The opening chapter provides an overview of drug discov-
ery and development. This serves as the foundation for the following 12
chapters that describe the various functions involved in drug discovery
and development. The early phases of drug discovery are described in
detail through the discussions of important topics such as target identi-
fication, target validation, lead identification, multidimensional lead
optimization, pharmacokinetics, preclinical pharmacodynamics, and
early toxicology. This is followed by discussions of preclinical activities,
clinical trial design, biomarkers, and translational medicine. Each chap-
ter builds on the previous chapters and this approach provides the
readers with an integrated view of the various multidisciplinary func-
tions required for the drug discovery and development process.
Chapter 12, Organizational Consideration and Trends in the
Pharmaceutical Industry, and Chapter 13, Intellectual Property and
Patents in Drug Discovery, describe two important topics essential for
running an effective pharmaceutical R&D business, organizational
structure and patent protection. These chapters give the reader a true
understanding of the organizational structure required for the success-
ful management of research and development organizations and the
importance of protecting intellectual property to ensure a good return
on investment. Patent protection is the life blood of the pharmaceutical
and biotech industries, and at the same time a source of innovation for
new discoveries. Patents ensure the sharing of discoveries and innova-
tions that might otherwise be kept as trade secrets. In the final chapter,
case studies demonstrating the practical application of the concepts and
principles described in the previous chapters are provided. These vign-
ettes also describe important lessons learned in each case, some of
which changed the way modern drug-discovery research and develop-
ment programs are executed.
 Foreword xvii

Although there are numerous textbooks that discuss various aspects

of the drug discovery and development process, none of them provides
a comprehensive view of the process. Basic Principles in Drug Discovery
and Development is unique in its comprehensive approach to this com-
plex endeavor. In writing this textbook, Dr. Blass has provided an
important new tool for the education of the next generation and a valu-
able resource for people with a vested interest in the identification and
commercialization of novel medications.

Magid Abou-Gharbia, PhD, FRSC

Laura H. Carnell Professor
Director Moulder Center for Drug Discovery Research
School of Pharmacy, Temple University
Philadelphia, PA, United States
 C H A P T E R

1
Drug discovery and
development: An overview of
modern methods and principles

Over the course of the last two centuries, modern medicines have
improved the lives of countless patients. Diseases and conditions that
were once deemed incurable or fatal have been conquered with thera-
peutic agent designed to extend and improve quality of life. The most
recent, and perhaps most notable of these accomplishments is the transi-
tion seen in the consequences of infection with human immuno-
deficiency virus (HIV), the virus known to cause acquired
immunodeficiency syndrome (AIDS).1 When the virus was first identi-
fied by two research groups in 1983,2 there were few antiviral agents
available, none provided effective treatment for HIV infection, and
infection progressed rapidly to AIDS and death by opportunistic infec-
tion. By 1987, AZTs (Retrovirs and Azidothymidine; Fig. 1.1), the first
nucleoside reverse transcriptase inhibitor (NRTI), was approved for
clinical application for the treatment of HIV infection,3 and additional
treatment options were developed through the next three decades. New
NRTIs such as Vireads (Tenofovir)4 and Zeffixs (Lamivudine)5
(Fig. 1.1) that shared AZT’s mechanism of action (phosphorylation,
incorporation into a growing DNA chain, and chain termination)
expanded this class of HIV drugs. The development of non-NRTIs such
as Viramunes (Nevirapine)6 and Doravirines (Pifeltro)7 (Fig. 1.1) fur-
ther advanced HIV therapy and demonstrated that reversible, allosteric
inhibition (enzyme inhibition accomplished through drug binding at a
site other than the catalytic site, see Chapter 3) of reverse transcriptase
was a viable approach. HIV protease inhibitors such as Viracepts
(Nelfinavir),8 Norvirs (Ritonavir),9 and Crixivans (Indinavir)10 entered
the market at the beginning in the mid-1990s, adding a new dimension
to HIV therapy. At the same time, multidrug cocktail treatment

Basic Principles of Drug Discovery and Development

DOI: https://doi.org/10.1016/B978-0-12-817214-8.00001-4 1 © 2021 Elsevier Inc. All rights reserved.
2 1. Drug discovery and development: An overview of modern methods and principles

NH2 O
OH O
H HN
N N S N O CN
O H N NH2 N
HO OH HN
N O N P O N N
N N
N3 NH O O O N N CF3
O OH O
Cl
® ®
AZT Viread® Zeffix Viramune® Doravirine®
(Retrovir) (Tenofovir) (Lamivudine) (Nevirapine) (Pifeltro)

O
O
N N OH HN O
S HN O H O
O HO NH
O S
N N N
N N O N H
H H N OH N
OH H
S
H
OH
Viracept® Norvir® Crixivan® N

(Nelfinavir) (Ritonavir) (Indinavir)

O O O OH OH O H
N N O F F F F O
N N N N N
H H H H
O N N N N N
OH F O O
H H H
O O F O
® ®
Raltegravir Dolutegravir Bictegravir®
(Isentress) (Tivicay) (GS-9883)

FIGURE 1.1 Reverse transcriptase was the first enzyme successfully targeted in a drug
discovery program that focused on developing treatment options for HIV infection and
AIDS. AZTs (Retrovir), Vireads (Tenofovir), and Zeffixs (Lamivudine) are nucleoside
inhibitors of this important enzyme that terminate DNA chain growth, while Doravirines
(Pifeltro) is a non-nucleoside inhibitor of reverse transcriptase that reversibly binds to an
allosteric site of the target. HIV protease, another enzyme critical to the progression of
HIV and AIDS, has also been the subject of intense study. The antiviral agents Viracepts
(Nelfinavir), Norvirs (Ritonavir), and Crixivans (Indinavir) are HIV protease inhibitors
that were developed for the treatment of HIV infection and AIDS. HIV integrase inhibitors
such as Raltegravirs (Isentress), Dolutegravirs (Tivicay), and Bictegravirs (GS-9883) were
also developed for the treatment of HIV. AIDS, Acquired immunodeficiency syndrome;
HIV, human immunodeficiency virus.

regimens, also known as highly active antiretroviral therapy,11 were

introduced, further enhancing treatment options, culminating in the
development of all in one fixed combination medications such as
Compleras12 and Stribilds.13 By the turn of the 21st century, yet
another class of HIV therapies began to reach the market. HIV integrase
inhibitors such as Raltegravirs (Isentress),14 Dolutegravirs (Tivicay),15
and Bictegravirs (GS-9883)16 (Fig. 1.1) became available to patients as
individual drugs or as parts of the combination therapies Triumeqs
(Dolutegravir/Lamivudine 3TC/Abacavir)17 and Biktarvys (Bictegravir/
Emtricitabine/Tenofovir alafenamide).18 While additional progress is
clearly still required, it is clear that modern drug discovery and devel-
opment changed the course of the AIDS epidemic, allowing patients
who were once given a death sentence to lead productive lives.19
Cancer treatment has seen a similar transition, as survival rates for
many types of cancer have dramatically improved as a result of the

Basic Principles of Drug Discovery and Development

 Drug discovery and development: An overview of modern methods and principles 3

discovery and development of novel therapeutic agents. In the

United States, overall cancer death rates have declined 11.4%
between 1950 and 2009, and progress against some specific cancer
types has been substantial. Breast cancer, prostate cancer, and mela-
noma, for example, have seen significant increases in their 5-year sur-
vival rates over the same period. The 5-year survival rates for breast
cancer increased from 60% to 91%, while the survival rates for pros-
tate cancer increased from 43% to over 99%, and melanoma survival
rose from 49% to 93%.20 A significant portion of the improved clinical
outcomes in cancer can be attributed to improved chemotherapeutic
agents. The identification of antitumor natural products and
natural product analogs such as Taxols (Paclitaxel),21 Velbans
(Vinblastine),22 Adriamycins (Doxorubicin),23 and Hycamtins
(Topotecan)24 have clearly demonstrated the importance of natural
products in modern medicine, while the development of small mole-
cule kinase inhibitors such as Gleevecs (Imatinib),25 Tasignas
(Nilotinib),26 and Tarcevas (Erlotinib)27 provide clear evidence of the
power of modern drug discovery techniques (Fig. 1.2).
Much work remains to be done; however, as statistics from the
American Cancer Society indicate that in 2018, over 609,000 people will
die from cancer in the U.S. alone, and that the 2015 U.S. direct medical
care costs exceeded $80 billion. In addition, the 5-year survival rates for
cancers of the liver (18%), esophagus (18%), lungs (18%), and pancreas
(8%) are all low.28 Newer small molecule therapeutics such as
Vizimpros (Dacomitinib),29 Zejulas (Niraparib),30 and Alunbrigs
(Brigatinib)31 (Fig. 1.3) and biotherapeutics such as Keytrudas
(Pembrolizumab) (Fig. 1.3),32 Bavencios (Avelumab),33 and Opdivos
(Nivolumab)34 will almost certainly lead to further improvements in
cancer survival rates.
The treatment of cardiovascular disease has also seen dramatic
improvements in the wake of the discovery of a multitude of therapeu-
tic agents designed to mitigate symptoms or prevent the underlying
causes of the disease. A myriad of treatments has been developed to
address hypertension, also known as “The silent killer” because of its
asymptomatic nature, leading to improvements in both the quality of
life and life expectancy of patients. Diuretics (e.g., Midamors
(Amiloride),35 Lozols (Indapamide)),36 β-blockers (e.g., Tenoretics
(Atenolol),37 Inderals (Propranolol)),38 and angiotensin-converting
enzymes (ACE) inhibitors (e.g., Capotens (Captopril),39 Vasotecs
(Enalapril))40 are just a few of the types of treatments currently available
to lower blood pressure and keep cardiovascular disease at bay.
Revolutionary changes occurred in the prevention of cardiovascular dis-
ease with the introduction of HMG-CoA reductase inhibitors, also
known as statins.41 Lipitors (Atorvastatin),42 Zocors (Simvastatin),43

Basic Principles of Drug Discovery and Development

 O OH
O O OH O OH O N
N OH
N OH HO O
O NH O H N
O N O H
H H H O N
O O O O OH O O NH2
HO O O OH O
OH
N
O
O O O O
O OH
OH O
NH2

Taxol® Velban® Adriamycin® Hycamtin®

(Paclitaxel) (Vinblastine) (Doxorubicin) (Topotecan)
O
O
HN
NH
O N
N O
N NH
NH O N
N O
N F
N HN
N N N F
F N
N

Gleevac® Tasigna® Tarceva®

(Imatinib) (Nilotinib) (Erlotinib)
FIGURE 1.2 The natural products Taxols (Paclitaxel), Velbans (Vinblastine), Adriamycins (Doxorubicin), and Hycamtins (Topotecan) are exem-
plary natural products that have been developed for the treatment of cancer, while Gleevecs (Imatinib), Tasignas (Nilotinib), and Tarcevas
(Erlotinib) were developed for the treatment of cancer through the application of modern drug discovery programs.
 Drug discovery and development: An overview of modern methods and principles 5

O H2N O
P
H H
N N N N
N
N
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N
Alunbrig® Zejula®
N (Niraparib)
(Brigatinib)
F

HN Cl
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N
N N
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Vizimpro® Keytruda®
(Dacomitinib) (Pembrolizumab)

FIGURE 1.3 Vizimpros (Dacomitinib) was approved in 2018 for the treatment of meta-
static non-small cell lung cancer. Zejulas (Niraparib) was approved in 2017 for the treatment
of epithelial ovarian, fallopian tube, and primary peritoneal cancers. Alunbrigs (Brigatinib)
was approved in 2017 for the treatment of metastatic non-small cell lung cancer. Keytrudas
(Pembrolizumab) was approved in 2014 for the treatment of advanced melanoma.

H2N Cl OH
O N H OH
O H O N H
H2N NH2 N O O N
S N
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O O H2N
H2N Cl
Midamor® Lozol® Tenoretic® Inderal®
(Amiloride) (Indapamide) (Atenolol) (Propranolol)
HO
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® ® ®
Capoten Vasotec Zocor Lipitor®
(Captopril) (Enalapril) (Simvastatin) (Atorvastatin)

FIGURE 1.4 The diuretics Midamors (Amiloride) and Lozols (Indapamide), the
β-blockers Tenoretics (Atenolol) and Inderals (Propranolol), the ACE inhibitors Capotens
(Captopril), Vasotecs (Enalapril), and the HMGCoA reductase inhibitors Lipitors
(Atorvastatin) and Zocors (Simvastatin) have significantly improved the treatment of car-
diovascular disease. ACE, Angiotensin-converting enzyme.

and a number of related compounds have demonstrated a remarkable

capacity to lower cholesterol levels, a major risk factor associated with
cardiovascular disease (Fig. 1.4).44 The introduction of monoclonal anti-
bodies Praluents (Alirocumab) and Repathas (Evolocumab)45 further
advanced the treatment of cardiovascular disease. These agents target
proprotein convertase subtilisin/kexin type 9 (PCSK9), a key protein in

Basic Principles of Drug Discovery and Development

Another random document with
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'Sketches and Impressions' of Thomas Goodwin, published in 1887,
the following note on the subject: 'The Euterpean, an amateur
orchestra, was already an old organization half a century ago. It had
been well managed, and owned a small library and several valuable
instruments.... I have a program of its forty-eighth anniversary
concert, given January 21, 1847, which would carry its organization
back to the last century.' From the fact that the Euterpean Society
does not appear among the musical societies in the directory of
1799, Mr. Sonneck is inclined to the opinion that the society was
founded on January 21, 1800.

Probably in New York and elsewhere in America there were a

number of convivial clubs in which music, especially the singing of
glees and catches, occupied an important place. The frequency of
such organizations in England is an argument in favor of the
assumption, for English life was reproduced very much in detail by
the American colonists. It is not surprising that they escaped mention
in the contemporary press, as their activities were not of any public
interest. An exception must be made in favor of the Columbian
Anacreontic Society, which was modelled upon the famous
Anacreontic Society of London. The latter is of special interest to
Americans, since it furnished indirectly the music of 'The Star
Spangled Banner.' The New York version of the society probably was
more innocuous than its English model, though its affairs must have
been marked by a robust jolity. It was founded by John Hodgkinson,
a former member of the London Anacreontic Society, whose
excellent musical endowments and achievements did not prevent
him from being a faithful worshipper of Bacchus, and possibly it
numbered also in its membership other graduates of its English
prototype. The exact date of its foundation is not known, but it
certainly existed in 1795, as we glean from the following item in a
concert program of that year:

'Collini's Odes on the Passions (!), to be spoken by Mr. Hodgkinson.

With music representative of each passion; as performed at the
Anacreontic Society, composed by J. Hewitt.' This, Mr. Sonneck
notes, 'is in all probability the earliest example of melodramatic
music composed in America.' Unfortunately we have no other data
on the nature of the music performed at the concerts of the society.
These were held usually at the Tontine Coffee House, and it may be
assumed that they were devoted chiefly to catches, glees, and other
songs similar to those performed by the English society, but perhaps
not so intimately frank. Unlike the English society, but curiously like
every American stag society, before or since, the Columbian
Anacreontic held an annual ladies' night. The custom carries an
unpleasantly philistine flavor, which is further emphasized when we
read an announcement that such members of the society as chose
to attend a benefit performance for John Hodgkinson would be
accommodated in the 'Shakespeare Box' and would 'wear their
badges.' But in spite of all this it seems to have been of some value
in the musical life of New York.

II
During the first half of the nineteenth century the chief musical
societies in New York seem to have been the New York Choral
Society, the Philharmonic Society, the Euterpean Society, the Handel
and Haydn Society, The Musical Fund, and the Sacred Music
Society. Of the Euterpean Society we have already spoken as
having been founded probably in 1800. Apparently it was composed
chiefly of wealthy amateurs and was somewhat dilettante in its
activities. A contemporary critic thus arraigns it: 'This society, from its
long standing, the respectability of its officers, and the individual
talent of its members, might possess the most extensive influence in
the musical community. It has in its possession funds, and the
largest library of instrumental music in the country; and yet, with all
these advantages on its side, what has the Euterpean done, or what
does it do? It can be summed up in a few words. A few of its
members meet every Friday evening and play overtures and
symphonies; and every year they give an indifferent concert and a
ball, the last of which is the chief attraction. Now, we ask the
Euterpean if, like a horse in a mill, they are forever to pursue this
eternal round?'

The Euterpean did not continue that or any other course for very
long, but, whatever justice there may have been in the foregoing
criticisms, it was certainly the only instrumental music society in New
York during the years immediately preceding the advent of the
Philharmonic. Possibly its annual concert was 'indifferent,' but the
program of 1839, quoted by Dr. Ritter, which includes compositions
of Herold, Auber, Bellini, Boehm, Purcell, Rossini, and Thalberg,
would argue the contrary.[36] The orchestra was of sufficiently good
symphonic proportions. It consisted of six first violins, five second
violins, four tenors, three 'celli, two contrabasses, four flutes, two
oboes, two clarinets, two bassoons, four horns, two trumpets, three
trombones, kettle drums, drum and cymbals. Apparently the
principals in the orchestra of the Euterpean lacked zeal and
enterprise, but, whatever their faults, we are justified in looking upon
the society as the parent of the Philharmonic and as an important
factor in the development of orchestral music in New York.

Of this Philharmonic Society, which succeeded the Euterpean and

which is still flourishing, we shall speak in a later chapter. As far as
we can discover it had nothing to do with the earlier society of the
same name which was founded in 1799 of the junction between the
Harmonical and the St. Cecilia societies. The earlier Philharmonic is
somewhat elusive. If the occasional allusions to a Philharmonic
Society during the first decades of the nineteenth century referred to
the same organization, it probably existed until about 1829. There is
a possibility, however, that the original Philharmonic failed and that
various attempts were made to form other societies under the same
name. Dr. Ritter says that the Musical Fund, organized about 1828,
was the successor to a Philharmonic, the object of which was 'to
promote the cultivation of the science of music; to afford facilities for
the exhibition of talent, and its advancement to fair competition
among the profession and amateurs.' As the Musical Fund gave
monthly rehearsals for 'the display of glee and solo talent,' it may be
inferred that the Philharmonic was concerned mainly if not altogether
with vocal music; but we have been unable to discover any evidence
which would show that the two societies had anything in common.

The New York Choral Society, which devoted its energies to sacred
music, seems to have done very notable work during the short time it
lasted. It was founded in 1823, chiefly by Episcopal clergymen, and
its first grand concert, given at St. George's Church on Beekman
Street in 1824, is interesting enough to deserve citation:

First Part

Overture Jomelli
Air: 'Comfort ye my people,' from the 'Messiah' Handel
Chorus: Motetto, 'O God, when thou appearest' Mozart
Air: 'Thou didst not leave,' 'Messiah' Handel
Chorus: 'Lift up your hands' Handel
Duetto: 'Hear my prayer' Kent
Air: 'Oh! had I Jubal's Lyre' Handel
'Hallelujah Chorus,' from 'Mount of Olives,' Beethoven

Part Second

Overture from the Occasional Oratorio Handel

Recitative and Air Handel
Chorus: 'To thee Cherubim' Handel
Solo and Chorus: 'Thou art the King of Glory,' Handel
Air: 'Let the bright Seraphim'—'Judas Maccabæus' Handel
Chorus: 'Sing unto the Lord' Handel

Unfortunately contemporary critics were more enthusiastic than

discriminating and it is impossible to tell what sort of performance
was given of this excellent program. The effect of the forte parts of
Mozart's motetto, one critic asserts, 'was almost overwhelming to a
great number of the auditors, and will not be soon forgotten.' The
same gentleman quite loses his balance over the 'sublime and
majestic chorus from the oratorio of "Mount of Olives," which was
another of the full pieces that had never before been presented to
the musical public of this city. The connoisseurs and critics were
watching with considerable solicitude to hear the splendid effort of
genius, and which may be justly ranked among the first compositions
of the present day. We believe we may assert with confidence that
the expectations of all were fully realized, and, with regard to many
of the audience, far exceeded. The effect was indeed grand, and
was heightened by the trumpet of Mr. Petrie, and the kettle drums.'

In connection with Mr. Petrie's trumpet it may be of interest to note

the extraordinary predilection of New Yorkers at that time for brass
instruments. Dr. Ritter quotes the following from a contemporary
critic: 'The uncommon partiality our citizens manifest for the noisy
part of the orchestra has been lately much commented upon by
strangers. The trumpet and trombone occupy, in our concerts, the
posts of honor. True it is, Mr. Norton and Mr. Gambeti are excellent
performers—but we hear them in concerts too often. In England they
have Harper, a first-rate trumpet; and Germany has Schmidt, the
best trombone that ever existed. This gentleman visited England and
was heard occasionally, but at Niblo's Garden we will undertake to
say that more trumpet and trombone concertos were played last
season than have been heard in England and Germany for two
years. If Mr. Young adds himself to this triumvirate next season, we
may fairly expect New York will be blown away.'

The Choral Society seems to have been eclipsed and perhaps

absorbed by the New York Sacred Music Society, which was
founded in the same year. The latter owed its existence to the
somewhat peculiar circumstance of a strike among church
choristers. Considerable reputation attached to the choir of Zion
Church, which was known as the Zion Church Musical Association.
The association applied to the vestry for an increase of salary or
permission to give a concert. Their request was refused, and, after
some bickering, the choir resigned and formed The New York Sacred
Music Society. The history of this society is one of brilliant
accomplishment. At first its means and its membership were limited,
and its artistic ambitions were hampered by the lackadaisical attitude
of most of its members, to whom the meeting room of the society
was merely 'a pleasant place in which to pass an evening, to see
their friends, and hear a little music.' Nevertheless, a few years after
its foundation it was already doing work of a standard that must give
it a notable place in the history of New York musical organizations. In
1827 it gave a concert for the benefit of the Greek patriots, with a
program on which figured the names of Handel, Mozart, Beethoven,
Arne, and Jomelli. There was an orchestra of twenty-seven, a chorus
of about sixty, and a number of distinguished soloists, which included
the famous Madame Malibran. 'From this period,' says the New York
'Musical Journal,' 'the history of the progress of the highest species
of sacred music in this city is identified with the history of the society.'

Four years later the Sacred Music Society produced the 'Messiah' in
its entirety, under the leadership of Uriah C. Hill, whom we shall have
occasion to meet later. There was an orchestra of thirty-eight
instruments and a chorus of seventy-four voices. Encouraged by its
success it gave Haydn's 'Te Deum' and 'Creation,' and in 1838 it
produced Mendelssohn's 'St. Paul'—only two years after that work
had made its first appearance at Düsseldorf. For reasons which we
are unable to discover the Sacred Music Society ceased to exist in
1849. Possibly the musical public of New York were not overly
inclined toward oratorio, and possibly also the society suffered from
the competition of a number of rival organizations. Most of these,
such as 'The Academy of Church Music,' were formed out of church
choirs and very evidently aspired to rival the fame of the Sacred
Music Society. None of them, however, attained any success. Their
effect, indeed, was if anything, pernicious, for what New York then
needed in its musical affairs was concentration rather than
expansion.

For a short time New York possessed a Handel and Haydn Society
which originated in a number of oratorio performances gotten up to
finance the rebuilding of the Zion Church. This was before the day of
the Sacred Music Society. The Musical Fund, already mentioned,
seems to have been chiefly an orchestral organization,
notwithstanding the fact that, as Dr. Ritter points out, it gave monthly
rehearsals for 'the display of the glee and solo talent' of the city. A
concert given by it in 1830 included the overture to Mozart's 'Magic
Flute,' an overture of Winter, a pianoforte solo, a clarinet concerto,
and a trumpet concerto(!). We find that at its concert in 1836 the
Musical Fund had a very well balanced orchestra of thirty-eight
instruments and performed, among other things, the overtures to
Rossini's 'Sémiramide' and 'William Tell.' Handel, Haydn, Mozart,
Gluck, Beethoven, Rossini, and Weber all figured on the society's
programs, and on one occasion it presented Beethoven's 'Eroica,'
arranged for septet.

About this time there seems to have been a number of musical

societies among the German population of New York, which was
beginning to assume large proportions. Chief of these was the
Concordia, which was devoted to the improvement of instrumental
and vocal music. For a short time the Concordia was conducted by
Daniel Schlesinger, a native of Hamburg and a pupil of Ferdinand
Ries, who exercised considerable influence on musical life in New
York during his few years in the city. Many semi-private clubs for the
cultivation of various branches of music also began to make their
appearance, but they are of no particular importance, except in so
far as they testify to the growth of a serious interest in musical
matters.

III
It is quite impossible to say when and where the first musical society
made its appearance in New England. Though both Mr. Elson and
Dr. Ritter assert that the Stoughton Musical Society was founded in
1786 its right of priority is not apparent. Even if it had its beginning in
the singing school which Billings taught at Stoughton in 1774, it still
must yield precedence to the St. Cecilia and Orpheus societies of
Charleston, the Orpheus Club of Philadelphia, and the Harmonic
Society of New York—all of which were in existence before the latter
date.

Mr. Sonneck thinks that some sort of musical society existed in

Boston as early as 1761. Certainly an Aretinian Society existed there
in 1782, as we know from the announcement of a concert in which it
took part. Apparently it was devoted to the cultivation of sacred
choral music. An organization known as the Musical Society was
founded in Boston some time before 1786. In that year it gave a
concert of 'Sacred Musick, vocal and instrumental—for the benefit
and relief of the poor prisoners confined in the jail of this town.'
Apparently William Selby was conductor of the society, at least
during the years 1786-88, and a regular series of subscription
concerts were given every season until 1790, when the society
seems to have gone out of existence. There must have been other
societies in Boston at the same time, for we find that the proceeds of
a concert held in 1787 were to be devoted to the rebuilding of the
Meeting House in Hollis Street, 'agreeably to the generous intentions
of the Musical Societies in this town who have projected this
concert.' Some of these may have been founded before the Musical
Society.

The Stoughton Society, of which so much has been made in the

histories, is of importance chiefly because it was the first society that
we know of which was formed among the people and not among
cultured amateurs and professional musicians. Otherwise it is of
slight interest. It did nothing particularly noteworthy and we cannot
even say that it was an organization of high artistic efficiency. The
fact that its nucleus was a singing class of Billings is hardly an
endorsement of its quality, for there is no evidence that Billings
possessed any qualifications as a trainer of choruses. He was still
primitive enough to include female voices in the tenor part.
Nevertheless, as Deacon Samuel Tolman informs us, the Stoughton
Musical Society was 'large and respectable' and was 'attended with
spirit.' Its fame was great throughout Massachusetts and only once
was its supremacy questioned. The incident is related by Mr. Elson
as follows: 'Many clergymen in following the good old fashion of
"exchanging pulpits," had become familiar with the excellent church
music of Stoughton, and sounded its praise abroad. The singers of
the first parish of Dorchester, Massachusetts, took umbrage at this
and challenged the Stoughton vocalists to a trial of skill. The gauntlet
was at once taken up, and the contest took place in a large hall in
Dorchester, many of the leading Bostonians coming out to witness it.
The Dorchester choristers were male and female, and had the
assistance of a bass viol. The Stoughton party consisted of twenty
selected male voices, without instruments, led by the president of the
Stoughton Musical Society, Elijah Dunbar, a man of dignified
presence and of excellent voice. The Dorchester singers began with
a new anthem. The Stoughtonians commenced with Jacob French's
"Heavenly Vision," the author of which was their fellow townsman.
When they finally sang, without books, Handel's "Hallelujah Chorus"
the Dorchestrians gave up the contest and gracefully acknowledged
defeat.' At least the choristers of Massachusetts were enthusiastic
and sincere, and for their enthusiasm and sincerity one can forgive
them many faults.

How many musical societies existed in Boston during the last years
of the eighteenth century we cannot say. There seems to have been
a number of them. In 1789, during the visit of Washington to Boston,
'an Oratorio or Concert of Sacred Musick' was given in which the
choruses of the oratorio of Jonah were sung by the Independent
Musical Society. There is no evidence of the dates at which this
society began or ended its existence, but it must have been a fairly
efficient organization. There was no lack of competent musicians in
Boston at that time, and choral singing especially seems to have
been in high favor with a goodly share of the population. The society
of the Sons of Apollo, which existed in 1795, was probably a vocal
organization also, though we know nothing about it. Boston
possessed a Philharmonic Society which was founded probably
before 1799. Possibly Gottlieb Graupner, one of the most prominent
figures in the early musical life of Boston, was among its founders,
and it seems likely that it was identical with the Philharmonic Society
which is supposed to have been founded by Graupner and his
friends in 1810 or 1811. According to Mr. J. S. Dwight, author of a
'History of Music in Boston,' the Philharmonic was 'simply a social
meeting, held on Saturday evenings, when, in their small way, they
practised Haydn's symphonies.' This statement, however, does not
square with the fact that the society gave regular concerts and was
described by the musical journal, 'Euterpeiad,' as a 'useful nursery of
music.' Its last concert took place in 1824 and apparently it went out
of existence in that year.

During the last few years of the eighteenth and the first decades of
the nineteenth centuries musical societies began to spring up in the
smaller cities throughout the country. Very little information
concerning them has come to light, but it is probable that research
will finally disclose a surprising amount of serious musical activity in
places which so far have escaped mention in our musical histories.
The impression that musical culture in early America was confined to
Boston, New York, Philadelphia, and Charleston has taken firm root
and is confirmed by most of the evidence on the subject which has
appeared. But research in American musical history has for the most
part been extremely superficial and determined in its direction by
preconceived impressions which are wholly one-sided. Such special
studies in early American musical history as have been made—
those of Mr. O. G. Sonneck, for example—have exploded many
longstanding fallacies and misconceptions and undoubtedly further
research will clear the field of other myths now generally accepted as
incontestable.

There was a St. Cæcilia Society at Newport, R. I., in 1793, and we

find mention in 1797 of the anniversary meeting of the Concord
Musical Society. What the nature of these societies was we can only
guess. They were undoubtedly conscious attempts to organize all
the music lovers of these towns into compact bodies for the better
promotion and enjoyment of their favorite art. It is our conviction that
dozens of such societies existed in the smaller towns throughout the
country. In fact, it would seem that sometimes several societies co-
existed within a very small area—at least in New England—and
formed themselves into associations. We have an instance in the
case of the Essex Musical Association of Massachusetts, which was
founded in 1797. A copy of its constitution is preserved in the Roston
Athenæum. In 1821 the 'Euterpeiad' woke up to the fact that there
was a very large amount of musical activity throughout the country.
'During the last week,' it says, 'we noticed the following musical
performances that were to take place in the present month of May: A
concert of sacred music by the Beethoven Society at Portland (Me.),
a grand concert at Augusta (Ga.), a select oratorio at Providence by
the Psallion Society, a grand concert of music by the Philadelphia
Musical Fund, the grand Oratorio the "Creation" by the Harmonic
Society of Baltimore, a performance of sacred music by the New
Hampshire Musical Society at Hanover, in Boston an instrumental
and vocal concert for the benefit of Mr. Ostinelli, and a public oratorio
by the Handel and Haydn Society.'

About this time there existed in Dartmouth College a Handel Society,

which is notable as having been the first serious attempt by an
American college to promote musical culture. It was also the last for
a considerable period. Concerning this society Dr. Ritter quotes the
following from a letter written to him by Dr. A. G. Brown, president of
Hamilton College: 'The aims of the society were of the best. A good
working library of the best musical works then attainable was
procured, including such works as the "Messiah," the "Creation," The
Handel and Haydn Society Collection of Anthems, the old Colony
Collection, and other music of like kind. This was carefully studied by
the Society, and at the regular weekly meetings carefully sung....
Members of the society were chosen after due examination, and
counted it an honor to be members of the association. Ladies were
admitted as honorary members. And I have never heard better
church-music than from that society at some period of its existence.
Its influence did not stop within the walls of the college, but was
widely diffused, and continued beyond college life.' Unfortunately its
influence did not continue for very long.
Building of the Handel and Haydn Society of Boston (1850)
Without doubt there were many musical societies in Boston during
the early years of the nineteenth century, but, with the exception of
the Philharmonic Society, we have been able to discover only the
Massachusetts Musical Society, formed in 1807 'for improving the
mode of performing sacred music.' It would appear that this society
confined its activities exclusively to hymns, with the natural result
that few members were attracted to it. It ceased to exist in 1810.
Whatever other societies may have existed in Boston were
completely overshadowed by the founding of the Handel and Haydn
Society in 1815. This famous organization antedates several of the
societies we have already mentioned, but the greater part of its
career is covered by a later period. We consequently defer treatment
of it to the chapter dealing with these important modern societies, of
which it may be said to have been the first.

W. D. D.
 FOOTNOTES:
[35] Until 1790, as we have previously noted, the name was spelled 'Cæcilia.'

[36] It must not, of course, be forgotten that a comparison between this and a
modern orchestral program would be unfair. The program was light, and
conspicuously ignored the great Germans, but it was good of its time and kind. It
included an oboe solo, which must have been a novelty to New Yorkers.
 CHAPTER V
THE BEGINNINGS OF OPERA

Scarcity of theatrical performances in America; Charleston and

Tony Aston; New York, Philadelphia, and elsewhere—The
Revolution and after; rivalry between New York and Philadelphia
—The New Orleans opera.

Accepting the year 1750 as the earliest in which indisputable records

appear of opera in New York, writers on American musical history
pass over the remainder of the century with a few brief references
and escape with evident relief to the arrival of García's Italian troupe
in 1825.[37] This willingness to let the dust lie undisturbed on certain
phases of our musical development is hardly justifiable in the present
instance, for undoubtedly these writers were well aware that opera in
America during the eighteenth century was not such an infrequent
and sporadic thing as to deserve no extended mention. Mr. H. E.
Krehbiel, in his anecdotic and entertaining 'Chapters of Opera,'
writes: 'There are traces of ballad opera in America in the early
decades of the eighteenth century, and there can exist no doubt at
all that French and Italian operas were given in some form, perhaps,
as a rule, in the adapted form which prevailed in the London theatres
until far into the nineteenth century, before the year 1800, in the
towns and cities of the Eastern seaboard which were in most active
communication with Great Britain.'

If ballad operas were known in America in the early

decades of the eighteenth century and French and Italian operas
were given before the beginning of the nineteenth, it is surely worth
while to consider what part they played in the musical life of the
country. The subject, of course, is bristling with difficulties.
Information is scarce and not easily accessible. Much of the difficulty
is due to the fact that before the nineteenth century there were no
opera companies, in our sense. Operatic performances were given
by regular theatrical companies whose repertory was made up partly
of straight drama and partly of opera. Artistic versatility was a
characteristic of the period, and performers like Mrs. Oldmixon and
Miss Broadhurst were prominent not only on the dramatic and
operatic stage, but also on the concert platform. Our search for the
beginnings of opera, therefore, lead us naturally to early records of
the American theatre, and an examination of these elucidates some
interesting facts.

I
The first mention of theatrical performances in America is found in
the whimsical autobiography of the mercurial Tony Aston
—'Gentleman, Lawyer, Poet, Actor, Soldier, Sailor, Exciseman,
Publican; in England, Scotland, Ireland, New York, East and West
Jersey, Maryland, Virginia (on both sides Cheesapeek), North and
South Carolina, South Florida, Bahamas, Jamaica, Hispaniola, and
often a Coaster by all the same.' In the 'beginning of Queen Anne's
reign,' he tells us, he arrived at Port Royal Harbor where Governor
Moore was about to start on an expedition against St. Augustine.
This was in September, 1702. Tony accompanied Moore and
returned with him to Charleston in January, 1703. 'Well,' he says, 'we
arrived in Charles-Town, full of Lice, Shame, Poverty, Nakedness
and Hunger:—I turned Player and Poet and wrote one Play on the
Subject of the Country.' We may assume, therefore, that Charleston
witnessed theatrical performances in 1703. In the same year the
redoubtable Tony went to New York. 'There,' he says, 'I lighted of my
old Acquaintance Jack Charlton, Fencing Master, ... after acting,
writing, courting, fighting that Winter ... my kind Captain Davis ...
gave me free passage for Virginia....' Apparently, then, there were
theatrical performances in New York in the winter of 1703-04.

Whether these and the performances in Charleston were the

beginning of the theatre in America, we cannot say, nor do we know
if they included operas. Quite probably they did. The autobiography
from which we have quoted prefaced the published edition of Tony
Aston's 'Fool's Opera' and it has been inferred that his work was
played during Aston's visit to America. As it was published several
years after his return to England there is not much reason to believe
that New York or Charleston heard it, but Aston's evident interest in
works of the kind would indicate that he exhibited his talent in such
entertainments while he was in this country. It may, however, be
pointed out that opera was not in high favor in England at that time.
Beginning with 'The Siege of Rhodes' in 1656 opera was the chief
form of theatrical entertainment until the end of the Commonwealth.
For some peculiar reason—perhaps Cromwell's love of music—it
was tolerated in spite of the ban on the theatres. But after the
Restoration the drama came into its own again, and with Congreve,
Wycherley, Vanburgh, and others catering brilliantly to the taste of
the times, opera was temporarily neglected. Interest in it revived
under Queen Anne, with the coming of Handel and the Italian opera,
but, except for the temporary vogue of ballad-opera, following the
production of 'The Beggar's Opera' in 1728, English opera failed to
attract the popular favor. Indeed, it never reached a point where it
deserved to attract favor. Except for a few weak efforts in the Italian
recitative style English opera before the ballad opera was chiefly
drama with incidental music. The idea was popular in Elizabethan
times, as we may see from Shakespeare's plays. In the operas of
the Commonwealth and Restoration periods the musical side was
more emphasized, but the play was the thing, and there was no
Shakespeare or Jonson or Marlowe or Beaumont and Fletcher to
endow the thing with life.

So that whatever operatic performances may have resulted from

Tony Aston's visit to America could not be of any importance, though
they might be of some historical interest. One wonders if Tony's
regrettable departure from these shores left America theatrically
barren. Many years pass before we discover any sign of life. Then
from Jones's 'Present State of Virginia,' published in London in 1724,
we learn that a playhouse existed in Williamsburg, Va., at least as
early as 1722. Ten years later New York saw the opening of a New
Theatre in the building of a gentleman with the explosive appellation
of Rip Van Dam. Its name would suggest that another theatre existed
previously in New York. We cannot say what operas, if any, were
given there, but probably the Gray-Pepusch 'Beggar's Opera,' Hill's
'The Devil to Pay,' and Fielding's 'Flora, or Hob in the Well,' were
produced. At this period the ballad opera was enjoying its vogue in
England, and fashions both on and off the English stage were
faithfully copied in America. Almost until the end of the century ballad
operas remained very popular in this country. They had very little in
common with opera as we understand it and have no real place in
the evolution of the art-form. The music rarely was written especially
for them, but was arranged from existing compositions, especially
from English, Irish, and Scotch folk-tunes. Occasionally the
'composer' showed real skill in making his adaptations, as Dr.
Pepusch did in the 'Beggar's Opera,' but more frequently still the
music was singularly inept and the whole entertainment bordered
closely on extravaganza.

We find that 'Flora, or Hob in the Well,' was performed at the

Courtroom, Charleston, in 1735, and that the New Theatre in the
same city also produced 'Flora,' as well as 'The Devil to Pay,' in
1736. New York probably was giving similar performances at the
same time, but we can discover nothing definite on the subject until
1739, when we note that at Henry Holt's Long Room there was
performed 'A New Pantomime Entertainment in Grotesque
Characters, call'd the Adventures of Harlequin and Scaramouch, or
the Spaniard Trick'd. To which will be added an Optick'—whatever
that was. A company of actors appeared in Philadelphia in 1749, but
their advent inspired the city magistrates to 'take the most effectual
measures for suppressing the disorder.' The unfortunate artists
whose presence constituted a disorder then went to New York,
where they fitted up a building of the Hon. Rip Van Dam as the
'Theatre in Nassau Street.' There, in 1750 and 1751, they gave a
number of operatic performances, including Fielding's 'Mock Doctor,'
'The Beggar's Opera,' 'The Devil to Pay,' Cibber's 'Damon and
Philida,' Fielding's 'Virgin Unmask'd,' 'Flora,' and 'Colin and Phœbe.'
In 1751 they went South and, as the New York Company of
Comedians, obtained from Acting Governor Lee of Virginia
permission to build a theatre in Williamsburg. They played at
Fredericksburg in 1752 and in the same year, as the Company of
Comedians from Virginia, opened the New Theatre in Annapolis,
Md., with 'The Beggar's Opera.' They also gave the 'Virgin
Unmask'd,' the 'Mock Doctor,' 'Damon and Philida,' and 'The Devil to
Pay.' Then, metamorphosed into the Company of Comedians from
Annapolis, they appeared in upper Marlborough, where they gave
'The Beggar's Opera,' 'With Instrumental Music to each Air, given by
a Set of private Gentlemen.' We have been unable to follow them
further. Part of the original New York company to which they
belonged remained in that city and formed the nucleus of a new
company which in 1751-52 gave a number of operas at the Nassau
Street Theatre, including Carey's 'Honest Yorkshireman.'

Hallam's London Company of Comedians, subsequently the

American Company and later the old American Company, continued
the work of supplying Americans with regular theatrical
performances, including operas. We have been unable to follow their
activities in detail. In 1765 New York heard the pantomime ballad
'Harlequin's Vagaries,' perhaps the 'Harlequin Faustus' of Rich, with
music by Gaillard. Three years later was given Bickerstaff's 'Love in
a Village,' the music adapted by Arne from his own compositions and
from the works of Handel, Boyce, Howard, Baildon, Festing,
Geminiani, Galuppi, Giardini, Paradies, Abos and Agus. Everything
was grist to the ballad-opera mill. Bickerstaff's 'The Maid of the Mill,'
with music by Dr. S. Arnold, was played in New York in 1775.

II
Theatrical activities were naturally curtailed severely during the war,
but with the establishment of peace there was a great revival. After
the Revolution, indeed, the popularity of the theatre became much
greater and more widespread than it ever had been before. And
coincident with the popularity of the theatre came the popularity of
opera. Even in Boston the old prejudice against the theatres began
to disappear, though the blue laws of 1750 were still in force. Several
attempts were made at various times to circumvent these laws by
presenting operas under the guise of concerts, and the resulting
performances must occasionally have been wonderfully concocted.
We find an announcement in 1770 of 'A vocal entertainment of three
acts. The songs (which are numerous) are taken from a new
celebrated opera, call'd "Lionel and Clarissa."' An entry in the diary
of John Rowe during the same year reads: 'In the evening I went to
the Concert Hall to hear Mr. Joan read the Beggar's Opera and sing
the songs.' In 1792 Alexander gave in Boston 'a musical
entertainment called the Poor Soldier delivered,' and from that time
forward the friends of opera in Boston met with no opposition, though
it was long before Boston became an operatic city.

In the meantime Maria Storer was winning fame throughout the

country as a ballad opera singer. Such pleasant and innocuous
pieces as 'Thomas and Sally,' 'Dorcas and Squire,' and 'Lionel and
Clarissa' were very popular at the time, and old favorites like the
'Beggar's Opera' and 'The Devil to Pay' held their own with a vitality
that was surprising. The fact is that the American people, exhausted
by the labor and suffering of the war, were in the state of mind now
generally ascribed to 'the tired business man,' and the English ballad
opera was just the sort of light entertainment they needed. English
opera retained its popularity, especially in New York, until well into
the nineteenth century; but from about the year 1790 it was forced to
compete with French and Italian opera introduced by refugees from
France and St. Domingo, and gradually it lost ground until eventually
it disappeared completely.

Between 1789 and 1793 there were given at concerts in Philadelphia

compositions by Rousseau, Dalayrac, Gluck, Paesiello, Monsigny,