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Preface
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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:
1. Background
2. Pharmacology
3. Structure–activity relationship
4. Pharmacokinetics and drug metabolism
5. Efficacy and safety
6. Syntheses
7. Summary
8. References
I am very m uch indebted to all contributing authors from both
industry and academia. Many of them are veterans and well-known
experts in medicinal chemistry. S ome 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.
Jack Li
Jie
Ann Arbor, Michigan
February 1, 2024
Contributing Authors
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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
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
200131,
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
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QuantX Biosciences
214 Carnegie Center, Suite 108
Princeton, NJ 08540, USA
Dr. Guiping Zhang
Genhouse Bio
Floor 4, Building No.8, No.1 Xinze
Road, SIP, Suzhou 215000, P. R. China
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. 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
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1
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________________________________________________________________________________
Nirmatrelvir (Paxlovid with Ritonavir): A 3-
Chymotrypsin-like Protease Inhibitor for
Treating SARS-CoV-2 Infection
Jie Jack Li
Chemistry and Pharmacology of Drug Discovery, First Edition. Edited by Jie Jack Li.
© 2025 John Wiley & Sons, Inc. Published 2025 by John Wiley & Sons, Inc.
4
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4
Chemistry and Pharmacology of Drug Discovery
1. Background
The coronavirus disease-2019 (COVID-19) pandemic began in December 2019. Since
then on, it has infected over 537 million people and led to more than 6.5 million deaths
worldwide.
Some 20 years ago in 2002, severe acute respiratory syndrome (SARS) flared
up. In order to discover drugs to treat SARS, Pfizer carried out a fluorescence resonance
energy transfer (FRET)-based substrate cleavage assay. PF-00835231 (3) was identified
as a potent inhibitor of 3-CL
out quickly, Pfizer subsequently discontinued the project.
pro
of recombinant SARS-CoV-1. But since SARS petered
2
After the explosion of COVID-19 in 2020, Pfizer prepared PF-00835231 (3)’s
phosphate prodrug PF-07304814 (4) in an effort to boost the solubility. But PF-07304814
(4) still lacked oral bioavailability and had to be given intravenously. Later on, Pfizer
discontinued clinical trials for PF-07304814 (4) when their orally bioavailable 3-CL
inhibitors became promising. After the discovery of orally bioavailable nirmatrelvir (1),
its combination drug with ritonavir (2), Paxlovid, was approved by the FDA in December
3
2021.
In November 2022, Shionogi received Japanese government’s approval for its
pro
oral 3-CL
inhibitor, ensitrelvir (5, Xocova), which is not a peptidomimetic and is orally
bioavailable drug by itself without adding a pharmaco-enhancer.
pro
4
5
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Chapter 1. Nirmatrelvir (Paxlovid)
2. Pharmacology
2.1. The Coronavirus
SARS-CoV-2 is a positive-sense single-stranded RNA (+ssRNA) virus surrounded by an
envelope. The virus’s genome (Figure
it has about 30,000 RNA nucleotides in total.
1) consists of 11 open reading frames (ORFs) and
At the left of Figure 1, located at the 5′-end of the genome are the first two open
reading frames (ORF1a and ORF1b) that occupy approximately two-thirds of the genome
and encode 16 nonstructural proteins. At the right, the other ORFs are located at the 3′end of the genome and encode four common structural proteins including spike (S),
envelop (E), membrane (M), and nucleocapsid (N) proteins. The E and M proteins are
responsible for the shape of the virus, while the S protein mediates receptor attachment
and viral and host cell membrane fusion. The nucleocapsid (N) protein binds to the viral
RNA and forms a ribonucleoprotein that is packaged in the virus envelope (Figure
Figure 1. Coronavirus RNA genome
2).
5
6
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ORF1a and ORF1b produce polyproteins 1a (pp1a, ~450 kDa) and 1b (pp1b,
~750 kDa), respectively, for which the lengths and amino acid sequences are rather
conserved among all known coronaviruses. Among the nonstructural proteins are two
very large polyproteins (pp1a and pp1b) that are cleaved by two or three viral proteases.
Chemistry and Pharmacology of Drug Discovery
Figure 2. Coronavirus’s structure and functions
6
2.2. The 3CL Protease
Historically, proteases have been tractable drug targets for treating a variety of diseases.
Drugs targeting proteases include angiotensin converting enzyme (ACE) inhibitors such
as enalapril (6, Vasotec) for treating hypertension; neuraminidase inhibitors for treating
influenza; dipeptidyl peptidase-4 (DPP-4) inhibitors such as vildagliptin (7, Galvus) for
treating type II diabetes; HIV protease inhibitors as represented by ritonavir (2) for
treating HIV/AIDS; and HCV NS3/4A serine protease inhibitors, e.g., boceprevir (8,
Victrelis) and narlaprevir (9, Arlansa), for treating HCV infection. Therefore, 3CL
protease is considered as a prominent target for antiviral drugs.
Almost all protease inhibitors are transition-state mimics that are
peptidomimetics resulted from truncation and de-peptization of endogenous substrates.
Influenza neuraminidase inhibitors are the exceptions. This strategy had paved the road
for the discovery of nirmatrelvir (1). In fact, some of nirmatrelvir (1)’s building blocks
were directly “borrowed” from older protease inhibitors such as DPP-4 inhibitor
vildagliptin (7) and HCV NS3/4A protease inhibitors boceprevir (8) and narlaprevir (9,
vide infra).
7
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Chapter 1. Nirmatrelvir (Paxlovid)
Coronavirus’s two cysteine proteases papain-like cysteine protease (PL
pro
are responsible for cleaving polyproteins. The combined proteolytic actions of 3-
3-CL
CL
pro
and PL
pro
produce various shorter, nonstructural proteins vital to viral replication
pro
) and
such as RNA-dependent RNA polymerase and helicase that are required in viral life
cycle. 3-CL
Figure
composed of two protomers that consist of three domains, namely I, II, and III (Figure
pro
itself cleaves two polyproteins (pp1a and pp1b) at 11 different sites (see
7
1).
Structurally, 3-CL
pro
is a three-domain cysteine protease. It is a homodimer
3).
The homodimer forms due to the interactions between the N-terminus of domain I + I
and the C-terminus of domain III. This dimer is reversible and more stable when a
substrate is bound. The catalytic dyad Cys145–His41 is located in a cleft between the
domains I and II, whereas domain III is just a cluster of helices. The protease is a highly
conserved key protease for SARS-CoV-2 replication and no relevant homologous protein
pro
with a similar cleavage site to 3CL
pro
development of 3CL
inhibitors offers great promise for treatment of COVID-19.7
has been identified in humans. Therefore,
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