Chemistry and Pharmacology of Drug Discovery (eBook)

Jie Jack Li (Herausgeber)

eBook Download: EPUB

2024
687 Seiten
Wiley (Verlag)
978-1-394-22514-9 (ISBN)

Infos

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 ?-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.

Jie Jack Li, PhD is the CSO of GenHouse Bio. Previously, he was VP of Discovery Chemistry at ChemPartner, an Associate Professor of Chemistry at the University of San Francisco, and a Medicinal Chemist at Pfizer and Bristol-Myers Squibb. He has authored or edited over 30 books, many published by Wiley.

Textauszug

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

Jie Jack Li

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-CLpro of recombinant SARS-CoV-1. But since SARS petered out quickly, Pfizer subsequently discontinued the project.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-CLpro 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 2021.3

In November 2022, Shionogi received Japanese government’s approval for its oral 3-CLpro inhibitor, ensitrelvir (5, Xocova), which is not a peptidomimetic and is orally bioavailable drug by itself without adding a pharmaco-enhancer.4

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 1) consists of 11 open reading frames (ORFs) and it has about 30,000 RNA nucleotides in total.

Figure 1 Coronavirus RNA genome

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 2).5

Figure 2 Coronavirus’s structure and functions

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.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).

Coronavirus’s two cysteine proteases papain-like cysteine protease (PLpro) and 3-CLpro are responsible for cleaving polyproteins. The combined proteolytic actions of 3-CLpro and PLpro produce various shorter, nonstructural proteins vital to viral replication such as RNA-dependent RNA polymerase and helicase that are required in viral life cycle. 3-CLpro itself cleaves two polyproteins (pp1a and pp1b) at 11 different sites (see Figure 1).7

Structurally, 3-CLpro is a three-domain cysteine protease. It is a homodimer composed of two protomers that consist of three domains, namely I, II, and III (Figure 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 with a similar cleavage site to 3CLpro has been identified in humans. Therefore, development of 3CLpro inhibitors offers great promise for treatment of COVID-19.7

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

Unlike the conventional Ser(Cys)–His–Asp(Glu) triad found in other chymotrypsin-like enzymes, 3-CLpro of SARS-CoV-2 has a catalytic dyad formed by His41 and Cys145 that catalyzes the hydrolysis of the peptide bond at highly specific sites of a polypeptide chain through a common nucleophilic-type reaction. It was suggested that a water molecule might complete the catalytic triad by mediating crucial interactions between His41 and other important conserved residues, such as His164 and Asp187.8

A nomenclature carton is shown below to better orient us with regard to the binding pockets of protease and substituents of endogenous ligands or protease inhibitors (Figure 4). In essence, a protease normally has an active catalytic site. It was defined that the first binding pocket on the left of the active site as S1 and the second on the left as S2 and so on. The first binding pocket on the right of the catalytic metal is defined as S1′ and the second one on the right as S2′. For the endogenous ligand in the form as a peptide chain, the fragment occupying the S1 pocket is defined as P1 region. Meanwhile, the peptide fragment that is occupying the S1′ pocket is known as the P1′ region. This is known as the Schechter–Berger nomenclature,9 which will be used throughout this chapter to illustrate drugs’ binding and structure–activity relationship (SAR), etc.

Figure 4 Schechter–Berger nomenclature for protease and its substrate-binding subsites

2.3. The Mechanism of Action of Nirmatrelvir

Nirmatrelvir (1) is a reversible covalent inhibitor of coronavirus’s 3CLpro, eliciting prolonged enzyme inhibition. The recovery of >50% 3CLpro activity after incubation with 1 indicates that inhibition of SARS-CoV-2 3CLpro is reversible.

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

The substrates for 3CLpro, pp1a and pp1b, share several common features including the omnipresence of a glutamine (Glu) residue at P1. No known human cysteine protease cleaves after Glu, thus offering potential selectivity for this viral target over the human proteome. Once nirmatrelvir (1) properly binds to the 3CLpro, cysteine-145 of the enzyme attacks the nitrile of the inhibitor in a fashion similar to the Pinner reaction to form a reversible S–C covalent bond on thioimidate 10 (Figure 5).10

Once 3CLpro is inhibited, the protease is then unable to cleave the polyproteins. As a consequence, the cell fails to produce various shorter, nonstructural proteins vital to viral replication.

3. Structure–Activity Relationship (SAR)

The 3-CLpro sequence between SARS-CoV-1 and SARS-CoV-2 is highly conserved. In fact, they are 100% identical in the catalytic domain that carries out polyprotein cleavage. Consequently, some previously discovered compounds developed over 15 years ago to treat SARS-CoV-1, such as PF-00835231 (3), showed high in vitro potency against SARS-CoV-2 as well.2,10

PF-00835231 (3) was a good starting point for lead optimization. But at first, let us examine the origin of the three key fragments on nirmatrelvir (1), namely, the pyrrolidone substituent at P1, the rigid bicyclic dimethylcyclopropylproline at P2 and the nitrile warhead at P1′.

3.1. The Pyrrolidone Substituent at P1

The pyrrolidone substituent in the P1 pocket has been ubiquitous in many 3-CLpro...

Produkt-Details

• Erscheint lt. Verlag: 23.8.2024
• Sprache: englisch
• Themenwelt: Naturwissenschaften ► Chemie
• Schlagworte: cancer drugs • CNS Drugs • drug design • drug development • Drug metabolism • drug process • drug safety • FDA approval • FDA drugs • infectious disease • Medical Chemistry • pharmaceuticals • pharma chemistry • Pharmacokinetics
• ISBN-10: 1-394-22514-8 / 1394225148
• ISBN-13: 978-1-394-22514-9 / 9781394225149