Chemistry and Pharmacology of Drug Discovery E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 569

Veröffentlichungsjahr: 2024

Beschreibung

Case studies of 20 successful FDA-approved drugs, from biological rationale to clinical efficacy studies and state-of-the-art applications

Chemistry and Pharmacology of Drug Discovery illustrates how chemistry, biology, pharmacokinetics, and a host of disciplines come together to produce successful medicines, discussing a total of 20 drugs that are all FDA-approved post 2021—some of which are first-in-class and revolutionary.

The four sections in this book cover Infectious Disease, Cancer Drugs, CNS Drugs, and Miscellaneous Drugs. Each chapter covers background material on the drug class and/or disease indication and key aspects relevant to the discovery of the drug, including structure-activity relationships, pharmacokinetics, drug metabolism, efficacy, and safety.

This book is contributed to by various veterans and well-known experts in medical chemistry, many of whom discovered the drugs they reviewed, leading to tremendous quality and depth of insight.

Some of the drugs covered in Chemistry and Pharmacology of Drug Discovery include:

• Nirmatrelvir (Paxlovid with Ritonavir), a 3-chymotrypsin-like protease inhibitor for treating SARS-CoV-2 infection
• Doravirine (Pifeltro), a third-generation non-nucleoside reverse transcriptase inhibitor for the treatment of HIV-1 infection
• Oteseconazole (Vivjoa), a CYP51 inhibitor for treating recurrent vulvovaginal candidiasis, and Rimegepant (Nurtec ODT), a CGRP antagonist for treating migraine
• Ciprofol (Cipepofol), a γ-Aminobutyric acid receptor agonist for induction of anesthesia, and Ozanimod (Zeposia), an S1P receptor antagonist for treating multiple sclerosis
• Deucravacitinib (Sotyktu), a first-in-class deuterated TYK2 inhibitor for the treatment of plaque psoriasis

Chemistry and Pharmacology of Drug Discovery serves as an excellent and highly authoritative learning resource for medicinal, organic, synthetic, and process chemists as well as research scientists in lead optimization and process development.

Leseprobe

Table of Contents

Cover

Table of Contents

Title Page

Copyright

Preface

Contributing Authors

Section I.: DRUGS TREATING INFECTIOUS DISEASES

1 Nirmatrelvir (Paxlovid with Ritonavir): A 3-Chymotrypsin-like Protease Inhibitor for Treating SARS-CoV-2 Infection

1. Background

2. Pharmacology

3. Structure–Activity Relationship (SAR)

4. Pharmacokinetics and Drug Metabolism

5. Efficacy and Safety

6. Synthesis

7. Summary

References

2 Doravirine (Pifeltro): A Third-Generation Non-Nucleoside Reverse Transcriptase Inhibitor as a Treatment of HIV-1 Infection

1. Background

2. Pharmacology

3. Structure–Activity Relationship (SAR)

4. Pharmacokinetics and Drug Metabolism

5. Efficacy and Safety

6. Synthesis

7. Summary

References

3 Cabotegravir (Vocabria): An HIV Integrase Strand Transfer Inhibitor for Treating HIV Infection

1. Background

2. Pharmacology

3. Structure–Activity Relationship (SAR)

4. Pharmacokinetics and Drug Metabolism

5. Efficacy and Safety

6. Synthesis

7. Summary

References

4 Lenacapavir (Sunlenca): A Long-acting HIV-1 Capsid Protein Inhibitor for Treating HIV Infection

1. Background

2. Pharmacology

3. Structure–Activity Relationship (SAR)

4. Pharmacokinetics and Drug Metabolism

5. Efficacy and Safety

6. Synthesis

7. Summary

References

5 Fostemsavir (Rukobia): An HIV-1 gp120-Directed Attachment Inhibitor for Treating AIDS

1. Background

2. Pharmacology

3. Structure–Activity Relationship (SAR)

4. Pharmacokinetics and Drug Metabolism

5. Efficacy and Safety

6. Synthesis

7. Summary

References

6 Oteseconazole (Vivjoa): A CYP51 Inhibitor for Treating Recurrent Vulvovaginal Candidiasis

1. Background

2. Pharmacology

3. Structure–Activity Relationship (SAR)

4. Pharmacokinetics and Drug Metabolism

5. Efficacy and Safety

6. Synthesis

7. Summary

References

Section II.: ONCOLOGY DRUGS

7 Futibatinib (Lytgobi): A Selective Irreversible FGFR1–4 Inhibitor

1 Background

2 Pharmacology

3 Structure–Activity Relationship (SAR)

4 Pharmacokinetics and Drug Metabolism

5 Efficacy and Safety

6 Synthesis

7 Summary

References

8 Pacritinib (Vonjo): A Dual JAK2/IRAK1 Inhibitor for Treating Myelofibrosis

1 Background

2 Pharmacology

3 Structure–Activity Relationship (SAR)

4 Pharmacokinetics and Drug Metabolism

5 Efficacy and Safety

6 Synthesis

7 Summary

References

9 Tucatinib (Tukysa): An Oral, Selective HER2 Inhibitor for the Treatment of HER2-Positive Solid Tumors

1 Background

2 Pharmacology

3 Pharmacokinetics and Drug Metabolism

4 Efficacy and Safety

5 Synthesis

6 Summary

References

10 Tazemetostat (Tazverik): An EZH2 Inhibitor for Treatment of Epithelioid Sarcoma and Follicular Lymphoma

1. Background

2. Pharmacology

3. Structure–Activity Relationship (SAR)

4 Pharmacokinetics and Drug Metabolism

5 Efficacy and Safety

6 Synthesis

7 Summary

References

Section III.: CNS DRUGS

11 Ozanimod (Zeposia): An S1P Receptor Modulator for Treating Multiple Sclerosis and Inflammatory Bowel Diseases

1. Background

2. Pharmacology

3. Drug Metabolism and Pharmacokinetics

4. Structure–Activity Relationship (SAR)

5. Efficacy and Safety

6. Synthesis

7. Summary

References

12 Ciprofol (Cipepofol): A γ-Aminobutyric Acid Receptor Agonist for Induction of Anesthesia

1. Background

2. Pharmacology

3. Structure–Activity Relationship (SAR)

4. Pharmacokinetics and drug metabolism

5. Efficacy and Safety

6. Synthesis

7. Summary

References

13 Rimegepant (Nurtec ODT): A CGRP Receptor Antagonist as a Treatment of Episodic Migraine

1. Background

2. Pharmacology

3. Structure–Activity Relationship (SAR)

4. Pharmacokinetics and Drug Metabolism

5. Efficacy and Safety

6. Synthesis

7. Summary

References

14 Daridorexant (Quviviq): An Antagonist of Orexin Receptors for Treating Insomnia

1. Background

2. Pharmacology

3. Structure–Activity Relationship (SAR)

4. Pharmacokinetics and Drug Metabolism

5. Efficacy and Safety

6. Synthesis

7. Summary

References

Section IV.: ANTI-INFLAMMATORY DRUGS

15 Deucravacitinib (Sotyktu): A First-in-Class Deuterated TYK2 Inhibitor for the Treatment of Plaque Psoriasis

1. Background

2. Pharmacology

3. Structure–Activity Relationship (SAR)

4. Pharmacokinetics and Drug Metabolism

5. Efficacy and Safety

6. Synthesis

7. Summary

References

Section V.: MISCELLANEOUS DRUGS

16 Bremelanotide (Vyleesi): A Melanocortin Receptor Agonist for Treating Female Hypoactive Sexual Desire Disorder

1. Background

2. Pharmacology

3. Structure–Activity Relationship (SAR)

4. Pharmacokinetics and Drug Metabolism

5. Efficacy and Safety

6. Synthesis

7. Summary

References

17 Odevixibat (Bylvay): A Selective Inhibitor of the Ileal Bile Acid Transporter

1. Background

2. Pharmacology

3. Early Inhibitors of the Ileal Bile Acid Transporter

4. Structure–Activity Relationship (SAR)

5. Pharmacokinetics and Drug Metabolism

6. Efficacy and Safety

7. Synthesis

8. Summary

References

Index

End User License Agreement

List of Tables

Chapter 2

Table 1 Key HIV-1 mutations

Table 2 Mutant Profile NNRTIs

Table 3 SAR for the Optimization of the 4-Position of the Pyridone Core...

Table 4 Structure-activity and solubility relationship for side chain replac...

Table 5 Pharmacokinetics of NNRTIs

Chapter 3

Table 1 Effects of tricyclic carbamoyl pyridones...

Table 2 Preclinical pharmacokinetic parameters for 14 and 1

Table 3 Virological profile of cabotegravir (1) and dolutegravir (14)

Chapter 5

Table 1 PK profile of BMS-043 and temsavir in rat

Table 2 PK profiles of temsavir and BMS-043 in higher species

Chapter 6

Table 1 A summary of human CYP450 enzyme inhibition of several antifungal dr...

Table 2 All SAR information taken from Hoekstra et al.

49

...

Table 3 All SAR information taken from Hoekstra et al.

49

...

Table 4 All SAR information taken from Hoekstra et al.

49

...

Table 5 Efficacy of oteseconazole (1) in Phase 3 Clinical Trials

51

Table 6 MIC

50

of oteseconazole (1) and fluconazole (14) against clinical iso...

Chapter 7

Table 1 Kinase inhibitory activities of 3-Quinoline analogues...

Table 2 Kinase inhibitory activities of 3,5-dimethoxybenzene analogues Kinas...

Table 3 Kinase inhibitory activities of alkyne analogues Kinase inhibition I...

Table 4 Cellular potency of alkyne analogues Growth inhibition IC

50

(nM)

Table 5 DMPK profile of representative compounds

Chapter 8

Table 1

In vitro

kinase spectrum of pacritinib (1)

Table 2 Search for a suitable linker for selectivity toward JAK2...

Table 3 SAR of optimization solubility...

Table 4 SAR Exploration of aromatic ring substitutions with small groups...

Table 5 ADME profile of pacritinib (1)

Chapter 10

Table 1 Optimization of 5,6-bicylic core...

Table 2 Optimization of substituted benzene core...

Table 3 Optimization of pyridone warhead...

Chapter 11

Table 1 S1PR1 modulators, chemical structures, pEC

50

values, indication and ...

Chapter 12

Table 1 Approved 2,6-substituted phenol for anesthesia...

Table 2 Clinical trials of ciprofol (1)

Table 3

In vivo

studies on sedation and SAR study of 2,6-disubstituted pheno...

Table 4

In vitro

activity on sedation and SAR study of 2,6-disubstituted phe...

Table 5 Pharmacokinetic parameters of propofol (2), ciprofol (1) and (

R, R

)-

Table 6 Pharmacokinetic parameters of ciprofol (1) after a single injection ...

Chapter 13

Table 1 Antagonists for CGRP and its receptors approved by the FDA

Chapter 14

Table 1 Final 2-vector library with pyrrolidine core

Table 2 Pharmacokinetic features of daridorexant (1)

Chapter 15

Table 1 Associated

in vitro

data comparing 11 and 12

Table 2

In vitro

data for select analogues from C3′

N

-methyl triazole series...

Table 3 Efficacy results in adults with moderate-to-severe plaque psoriasis ...

Chapter 16

Table 1 Sequences of human melanocortins

Table 2 Pharmacological properties of MCR subtypes

Chapter 17

Table 1 Evaluation of the C3, 4, and 5 chiral centers...

Table 2 Optimization of fused benzene ring substituents...

Table 3 Optimization of peptide chain substituents...

List of Illustrations

Chapter 1

Figure 1 Coronavirus RNA genome

Figure 2 Coronavirus’s structure and functions

Figure 3 The structure of coronavirus’s 3-CL protease, drawn from PDB 6UL7

Figure 4 Schechter–Berger nomenclature for protease and its substrate-bindin...

Figure 5 Reversible covalent bond between nirmatrelvir (1) and 3CL

pro

Chapter 2

Figure 1 The structure of the HIV

Figure 2 The central dogma of molecular biology

Figure 3 Single-point mutation of HIV-1 reverse transcriptase

Figure 4 The three-dimensional structure of HIV-1 reverse transcriptase, dra...

Figure 5 Doravirine (1) specifically targets the allosteric binding pocket o...

Chapter 3

Figure 1 The

in vivo

integration process

Figure 2 The two-metal-ion catalysis and inhibition mechanism.

Figure 3 HIV integrase structural domains.

Figure 4 A typical integrase strand transfer inhibitor binding to the cataly...

Figure 5 Allosteric HIV-1 integrase inhibitors targeting LEDGF/p75

Chapter 4

Figure 1 HIV capsid protein.

Figure 2 Schematic overview of the early stages of HIV-1 replication.

Figure 3 The X-ray crystal structure of the HIV-1 capsid hexamer bound to PF...

Figure 4 The X-ray crystal structure of the HIV-1 capsid hexamer bound to le...

Chapter 5

Figure 1 HIV AI blocks gp120 of HIV-1 binding to CD4 receptor (a) and HIV AI...

Figure 2 Optimization from BMS-216 to fostemsavir

Figure 3 Coplanarity model with C-linked heteroarenes

Figure 4 Coplanarity model with N-linked heteroarenes

Figure 5 Fostemsavir converted to temsavir in the presence of alkaline phosp...

Figure 6 Plasma exposure profiles of temsavir (BMS-626529) as temsavir and f...

Figure 7 Plasma exposure of temsavir following administration of fostemsavir...

Scheme 1 Discovery synthetic route towards temsavir (5)

Scheme 2 Alternative discovery synthetic route toward temsavir

Scheme 3 Preparation of fostemsavir-tris from temsavir

Scheme 4 Development route toward fostemsavir-tris

Chapter 6

Figure 1 Structure of nystatin (2) and amphotericin B (3)

Figure 2 Structure of naftifine (4) and terbinafine (5)

Figure 3 The structures of caspofungin (6) with molecular weight of 1093.31 ...

Figure 4 First generation azoles chlormidazole (8), clotrimazole (9), flutri...

Figure 5 The structures of ketoconazole (13) and 1,2,4-triazole drugs (14–17...

Figure 6 The function of CYP51 is to catalyze the stereo- and regio-selectiv...

Figure 7 The proposed step-wise mechanism of CYP51

24

,

47

Figure 8 Bench route synthesis of oteseconazole (1)

49

Figure 9 Installation of the tetrazole by use of a Claisen condensation reac...

Figure 10 Asymmetric Henry reaction of (42)

Figure 11 Reduction of nitrile before cyclization

Chapter 7

Figure 1 Schematic diagram of FGFRs and the structure of the FGFR extracellu...

Figure 2 X-ray crystal structure of TAS-120 (1) in complex with FGFR1(PDB; M...

Chapter 8

Figure 1 JAK/STAT pathway. Step 1: Cytokine binding, complex formation, acti...

Figure 2 Domain structure of JAKs

Figure 3 Compound 10e docked into the ATP-binding site of JAK2. Source: Will...

Figure 4 Schematic representation of molecular ionic structures of pacritini...

Chapter 9

Figure 1 Chemical structure of HER2 tyrosine kinase inhibitors lapatinib (2)...

Figure 2 The HER2 signaling pathway

Figure 3 Predominant metabolic pathway of tucatinib (1)

Scheme 1 Retro-synthetic analysis of tucatinib (1)

Scheme 2 Array BioPharma’s synthesis route of tucatinib (1)

Scheme 3 Mao’s synthetic route to tucatinib (1)

Scheme 4 Mao’s synthetic route to tucatinib (1)

Chapter 11

Figure 1 The structure of fingolimod

Figure 2 The structure of ozanimod (1)

Figure 3 The structure of sphingosine-1-phosphate

Figure 4 Structures of ozanimod’s major metabolites CC112273 (14) and CC1084...

Figure 5 S1PR1 in complex with ML056. Source: Adapted from Hanson et al.

124

....

Scheme 1 Racemic synthesis of ozanimod (1)

Scheme 2 Synthesis of enantiopure ozanimod (1) using a chiral sulfonamide au...

Scheme 3 Enantioselective synthesis of ozanimod (1)

Chapter 12

Figure 1 2,6-Disubstituted phenol anesthesia-propofol (2) analogs

Figure 2 Fluorine-substituted analogue

Figure 3 Structure–activity relationships (SAR) of alkylphenols as anestheti...

Figure 4 Loss of righting reflex (LORR) experiment

Figure 5 Proposed main metabolic pathways of ciprofol (1) in humans.

Figure 6 Haisco synthesis route to ciprofol (1)

Figure 7 Haisco synthesis route B to ciprofol (1)

Figure 8 Haisco synthesis route C to ciprofol (1)

Figure 9 Haisco kilogram-scale route for clinical ciprofol (1)

Chapter 13

Figure 1 Overview of migraine-specific medications and their possible target...

Figure 2 Potential drug resistance mechanisms to medications targeting CGRP...

Chapter 14

Figure 1 Diagram of the generation of Orexin A and Orexin B from prepro-orex...

Figure 2 Structure and properties of OX1/OX2 HTS hit

Figure 3 Influence of proline core chirality

Figure 4 Selected OX1R/OX2R agonists via scaffold hopping

Figure 5 Major metabolites of daridorexant (1).

Scheme 1 Medicinal chemistry synthesis route of daridorexant (1).

Chapter 15

Figure 1 Schematic representation of functional domains of the JAK family of...

Figure 2 Structures of select examples of first-generation clinically approv...

Figure 3 Schematic depicting prevention of receptor-mediated activation.

Figure 4 Proposed mechanism of action of deucravacitinib.

Figure 5 Left, high-throughput screen hit 7 for IL-23 inhibition; Right, str...

Figure 6 Close-up of the binding site highlighting key interactions made by

Figure 7 Left, structure and associated

in vitro

data for 9; Right, structur...

Figure 8 Structures and kinase selectivity of 11 and 12

Figure 9 Structure and associated

in vitro

/

in vivo

data for Compound 13

Figure 10 Profiles of 13, primary metabolite 14 and trideuteromethyl analog

Figure 11 Left, structure and associated

in vitro/in vivo

data for compound

Figure 12 Structure and associated

in vitro/in vivo

data for compounds 17 an...

Figure 13 X-ray crystal structure of 18 bound with TYK2 JH2, highlighting th...

Figure 14 Structure and associated

in vitro

data for compound 19

Figure 15 X-ray crystal structure of 1 bound with TYK2 JH2 showing key inter...

Scheme 1 Synthesis of intermediate 27

Scheme 2 Discovery synthesis of deucravacitinib (1)

Figure 16 Retrosynthetic analysis of 1

Scheme 3 First pass proof of concept for “acid route”

Scheme 4 Synthesis of aniline 33

Scheme 5 Synthesis of dichloropyridazine carboxylic acid salt 40-01

Scheme 6 Synthesis of carboxylic acid zinc salt 48

Scheme 7 Penultimate Step: Synthesis of carboxylic acid zinc salt 49

Scheme 8 Commercial API step: synthesis of 1

Scheme 9 Commercial process to deucravacitinib (1)

Chapter 16

Figure 1 Excitatory (+) and inhibitory (–) effects of neurotransmitters and ...

Figure 2 BMT (1), mechanism of action.

Figure 3 SAR of MCRs agonists

Scheme 1 Solid phase peptide synthesis of BMT (1)

Scheme 2 HMBA-Rink-Amide-AM-resin preparation

Scheme 3 Synthesis of BMT (1)

Chapter 17

Figure 1 Function of human ileal bile acid transporter (IBAT).

Guide

Cover

Table of Contents

Title Page

Copyright

Preface

Contributing Authors

Begin Reading

Index

End User License Agreement

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Chemistry and Pharmacology of Drug Discovery

Edited by

Jie Jack Li

Copyright © 2025 by John Wiley & Sons, Inc. All rights reserved, including rights for text and data mining and training of artificial technologies or similar technologies.

Published by John Wiley & Sons, Inc., Hoboken, New Jersey.Published simultaneously in Canada.

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Library of Congress Cataloging-in-Publication Data applied forHardback ISBN: 9781394225125

Cover Design: Wiley

Cover Image: Courtesy of Faridoon

Preface

Our first five installments Wiley’s Drug Synthesis Series, Contemporary Drug Synthesis, The Art of Drug Synthesis, Modern Drug Synthesis, Innovative Drug Synthesis, and Current Drug Synthesis were published in 2004, 2007, 2010, 2015, and 2022, respectively. They have been warmly received by the drug discovery community. The current title, Chemistry and Pharmacology of Drug Discovery, is our sixth installment of this series.

This book has five sections, reviewing a total of 17 drugs. Section I, “Drugs Treating Infectious Diseases,” covers six drugs; Section II, “Oncology Drugs,” reviews four drugs; Section III, “CNS Drugs,” covers four drugs; Section IV Anti-inflammatory Drugs, reviews only one drug; and Section V, “Miscellaneous Drugs,” covers two additional drugs.

Each chapter is divided into seven sections as before:

Background

Pharmacology

Structure–activity relationship

Pharmacokinetics and drug metabolism

Efficacy and safety

Syntheses

Summary

References

I am very much indebted to all contributing authors from both industry and academia. Many of them are veterans and well-known experts in medicinal chemistry. Some of them discovered the drugs that they reviewed. As a consequence, their work tremendously elevated the quality of this book as a teaching tool.

Meanwhile, I welcome your critique and suggestions so we can make this Wiley’s Drug Synthesis Series even more useful to the drug discovery/development community.

Jie Jack LiAnn Arbor, MichiganFebruary 1, 2024

Contributing Authors

Prof. Timothy A. Cernak

Department of Chemistry

University of Michigan

500 S State St.

Ann Arbor, MI 48109, USA

Dr. Dao-Qian Chen

STA, 90 Delin Road

Pudong New District, Shanghai 200131,

P. R. China

Prof. Ke Ding

State Key Laboratory of Chemical

Biology

Shanghai Institute of Organic Chemistry,

Chinese Academy of Sciences

345 Fenglin Road

Shanghai 200032, P. R. China

Dr. Faridoon

Genhouse Bio

Floor 4, Building No.8, No.1 Xinze

Road, SIP, Suzhou 215000, P. R. China

Prof. Timothy J. Hagen

Department of Chemistry and

Biochemistry

Northern Illinois University

Faraday Hall

DeKalb, IL 60115, USA

Charles L. Lail III

Department of Chemistry and

Biochemistry

Northern Illinois University

Faraday Hall

DeKalb, IL 60115, USA

Dr. Jie Jack Li

Genhouse Bio

Floor 4, Building No.8, No.1 Xinze

Road, SIP, Suzhou 215000, P. R. China

Dr. Xiang Li

Beijing Kawin Technology

5 Rongjing E. St

BDA, Beijing 100176, P. R. China

Dr. Guanglin Luo

Discovery Chemistry

Bristol-Myers Squibb Co.

3551 Lawrenceville Road

Lawrence Township, NJ 08648, USA

Dr. Daljit Matharu

Medicinal Chemistry

Sanofi

350 Water Street

Cambridge, MA 02141, USA

Andrew Outlaw

Department of Chemistry

University of Michigan

500 S State St

Ann Arbor, MI 48109, USA

Dr. Yan Wang

ChemPartner

280 Utah Avenue, Suite 100

South San Francisco, CA 94080, USA

Dr. Tao Wang

Beijing Kawin Technology

5 Rongjing E. St

BDA, Beijing 100176, P. R. China

Dr. Dexi Yang

QuantX Biosciences

214 Carnegie Center, Suite 108

Princeton, NJ 08540, USA

Dr. Shaohui Yu

NuChem Sciences

2350 Cohen Street, Suite 201

Ville St-Laurent, QC

H4R 2N6 Canada

Yuqi Lavender Zha

Sanegene Bio

Room 301, Building 2, Zone B, Phase III

of BioBAY, No.99 Jingu Road, SIP,

Suzhou 215000, P. R. China

Dr. Guiping Zhang

Genhouse Bio

Floor 4, Building No.8, No.1 Xinze

Road, SIP, Suzhou 215000, P. R. China

Dr. Ji Zhang

HEC Pharm R&D Center

Pharmaceutical Science

Dongguan, Guangdong, P. R. China

Ruheng Zhao

Department of Chemistry

University of Michigan

500 S State St

Ann Arbor, MI 48109, USA

Section I.DRUGS TREATING INFECTIOUS DISEASES

2Doravirine (Pifeltro): A Third-Generation Non-Nucleoside Reverse Transcriptase Inhibitor as a Treatment of HIV-1 Infection

Jie Jack Li

The coronavirus pandemic has wreaked havoc around the globe during the last few years. Yet, we must not forget that an epidemic has been going on for decades, i.e., the HIV/AIDS epidemic. From the beginning of the 1980s, AIDS is estimated to have killed more than 25 million worldwide. According to the United Nations’ statistics, nearly 40 million people were living with HIV in 2021.1 Notably, AIDS has replaced malaria and tuberculosis as the world’s deadliest infectious disease. Even today, the United States sees about 40,000 new infections annually.

The FDA’s approval of doravirine (Pifeltro, 1), a third-generation non-nucleoside reverse transcriptase inhibitor (NNRTI), in 2018 was timely to contribute to the WHO’s lofty goal of stopping the HIV/AIDS pandemic by 2030.

1. Background

Françoise Barré-Sinoussi and Luc Montagnier in France discovered the human immunodeficiency virus (HIV, Figure 1) in 1983 and were bestowed the Nobel Prize in 2008. The HIV encodes 15 proteins although only three of them have enzymatic activities: reverse transcriptase, protease and integrase. Nevertheless, even many nonenzymatic proteins have been successfully targeted as treatments of HIV/AIDS.

Figure 1 The structure of the HIV

Since the discovery of AZT (azidothymidine, Retrovir, 2) as the first effective treatment of AIDS, seven additional HIV-1 nucleoside reverse transcriptase inhibitors (NRTIs) have been approved by the FDA. They include GSK’s Lamivudine (3TC, Epivir, 3) and Gilead’s tenofovir disoproxil (Viread, 4) and emtricitabine (FTC, Emtriva, 5), respectively. TNRTIs are orthosteric inhibitors binding to the active site (DNA polymerase) of the reverse transcriptase (vide infra), a key viral enzyme that produces double-stranded viral DNA genomes from a single-stranded viral RNA genome. In short, NRTIs function as viral DNA chain terminators.2

NRTIs have become the workhorse of highly active antiretroviral therapy (HAART), also known as antiretroviral therapy (ART): cocktail HIV-1 drugs that have significantly contributed to transforming AIDS from a death sentence to a chronic infection that can be managed with medicine.

HIV protease inhibitors were among the earliest drugs specifically developed for treating AIDS (AZT was initially developed as a cancer drug in the 1960s). Ten HIV protease inhibitors are on the market including ritonavir (Norvir, 1996), fosamprenavir (2005) and darunavir (Prezista, 2006). They are peptidomimetics that work as “transition state mimics.” Their key hydroxyl group mimics the tetrahedral transition state of an amide bond of the polyprotein substrate being hydrolyzed by HIV protease.3