Discovery of a Potent Acyclic, Tripeptidic, Acyl Sulfonamide Inhibitor of Hepatitis C Virus NS3 Protease as a Back-up to Asunaprevir with the Potential for Once-Daily Dosing

Sun, Li‐Qiang; Mull, Eric; Zheng, Barbara; D’Andrea, Stanley V.; Zhao, Qian; Wang, Alan Xiangdong; Sin, Nancy L.; Venables, Brian L.; Sit, Sing‐Yuen; Chen, Yan; Chen, Jie; Cocuzza, Anthony J.; Bilder, Donna M.; Mathur, Arvind; Rampulla, Richard; Chen, Bang‐Chi; Palani, Theerthagiri; Ganesan, Sivakumar; Arunachalam, Pirama Nayagam; Falk, Paul; Levine, Steven M.; Chen, Chaoqun; Friborg, Jacques; Yu, Fei; Hernandez, Dennis; Sheaffer, Amy K.; Knipe, Jay O.; Han, Yong‐Hae; Schartman, Richard; Donoso, Maria; Mosure, Kathy; Sinz, Michael; Zvyaga, Tatyana; Rajamani, Ramkumar; Kish, Kevin; Tredup, Jeffrey; Klei, Herbert E.; Gao, Qi; Ng, Alicia; Mueller, Luciano; Grasela, Dennis M.; Adams, Stephen P.; Loy, James; Lévesque, Paul; Sun, Huabin; Shi, Hong; Sun, Lucy; Warner, W.; Li, Danshi; Zhu, Jialong; Wang, Ying-Kai; Fang, Hua; Cockett, Mark I.; Meanwell, Nicholas A.; McPhee, Fiona; Scola, Paul M.

doi:10.1021/acs.jmedchem.6b00821

Cited by 25 publications

(17 citation statements)

References 44 publications

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“…The S4 pocket is mostly nonpolar and can accommodate both hydrophobic and hydrophilic side chains in natural HCV substrates (40). However, prior structure-activity relationship (SAR) studies on macrocyclic and peptidic scaffolds show that hydrophobic moieties are associated with higher potencies (41)(42)(43)(44)(45)(46)(47)(48). Thus, the inhibitors designed using molecular modeling had hydrophobic P4 moieties extending into the S4 pocket toward D168.…”

Section: Resultsmentioning

confidence: 99%

Avoiding Drug Resistance by Substrate Envelope-Guided Design: Toward Potent and Robust HCV NS3/4A Protease Inhibitors

Matthew

Zephyr

Rao

et al. 2020

mBio

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Hepatitis C virus (HCV) infects millions of people worldwide, causing chronic liver disease that can lead to cirrhosis, hepatocellular carcinoma, and liver transplant. In the last several years, the advent of direct-acting antivirals, including NS3/4A protease inhibitors (PIs), has remarkably improved treatment outcomes of HCV-infected patients. However, selection of resistance-associated substitutions and polymorphisms among genotypes can lead to drug resistance and in some cases treatment failure. A proactive strategy to combat resistance is to constrain PIs within evolutionarily conserved regions in the protease active site. Designing PIs using the substrate envelope is a rational strategy to decrease the susceptibility to resistance by using the constraints of substrate recognition. We successfully designed two series of HCV NS3/4A PIs to leverage unexploited areas in the substrate envelope to improve potency, specifically against resistance-associated substitutions at D168. Our design strategy achieved better resistance profiles over both the FDA-approved NS3/4A PI grazoprevir and the parent compound against the clinically relevant D168A substitution. Crystallographic structural analysis and inhibition assays confirmed that optimally filling the substrate envelope is critical to improve inhibitor potency while avoiding resistance. Specifically, inhibitors that enhanced hydrophobic packing in the S4 pocket and avoided an energetically frustrated pocket performed the best. Thus, the HCV substrate envelope proved to be a powerful tool to design robust PIs, offering a strategy that can be translated to other targets for rational design of inhibitors with improved potency and resistance profiles. IMPORTANCE Despite significant progress, hepatitis C virus (HCV) continues to be a major health problem with millions of people infected worldwide and thousands dying annually due to resulting complications. Recent antiviral combinations can achieve >95% cure, but late diagnosis, low access to treatment, and treatment failure due to drug resistance continue to be roadblocks against eradication of the virus. We report the rational design of two series of HCV NS3/4A protease inhibitors with improved resistance profiles by exploiting evolutionarily constrained regions of the active site using the substrate envelope model. Optimally filling the S4 pocket is critical to avoid resistance and improve potency. Our results provide drug design strategies to avoid resistance that are applicable to other quickly evolving viral drug targets.

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Section: Resultsmentioning

confidence: 99%

Avoiding Drug Resistance by Substrate Envelope-Guided Design: Toward Potent and Robust HCV NS3/4A Protease Inhibitors

Matthew

Zephyr

Rao

et al. 2020

mBio

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“…Next we explored a sulfoxide–magnesium exchange–Negishi cross‐coupling protocol to form (hetero)aryl cyclopropanes which are important pharmacophores. [12c] There are no prior examples of cross‐coupling between aryl halides and cyclopropyl organometallics derived from cyclopropyl sulfoxides. [21c] We employed a protocol similar to that which we recently reported for aziridine sulfoxides,[22e] and were delighted to observe the successful Negishi cross‐coupling from both trans and cis ‐cyclopropane derivatives with aryl bromides (Scheme ).…”

Section: Resultsmentioning

confidence: 99%

“…The cyclopropane motif is highly significant in drug discovery as the 10 th most frequently found ring system in small molecule drugs , . It is also present in a variety of biologically active natural products and other medicinally‐important molecules (Figure ) , . Substituted cyclopropanes present a well‐defined 3‐dimensional shape, conformational rigidity, and electronic properties in between that of an alkene and a gem ‐dimethyl group, for example, as a result of the small strained ring structure.…”

Section: Introductionmentioning

confidence: 99%

Divergent Synthesis of Cyclopropane‐Containing Lead‐Like Compounds, Fragments and Building Blocks through a Cobalt Catalyzed Cyclopropanation of Phenyl Vinyl Sulfide

2017

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Cyclopropanes provide important design elements in medicinal chemistry and are widely present in drug compounds. Here we describe a strategy and extensive synthetic studies for the preparation of a diverse collection of cyclopropane‐containing lead‐like compounds, fragments and building blocks exploiting a single precursor. The bifunctional cyclopropane (E/Z)‐ethyl 2‐(phenylsulfanyl)‐cyclopropane‐1‐carboxylate was designed to allow derivatization through the ester and sulfide functionalities to topologically varied compounds designed to fit in desirable chemical space for drug discovery. A cobalt‐catalyzed cyclopropanation of phenyl vinyl sulfide affords these scaffolds on multigram scale. Divergent, orthogonal derivatization is achieved through hydrolysis, reduction, amidation and oxidation reactions as well as sulfoxide–magnesium exchange/functionalization. The cyclopropyl Grignard reagent formed from sulfoxide exchange is stable at 0 °C for > 2 h, which enables trapping with various electrophiles and Pd‐catalyzed Negishi cross‐coupling reactions. The library prepared, as well as a further virtual elaboration, is analyzed against parameters of lipophilicity (ALog P), MW and molecular shape by using the LLAMA (Lead‐Likeness and Molecular Analysis) software, to illustrate the success in generating lead‐like compounds and fragments.

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“…The addition of cyclopropyl-acyl sulfonamide showed 50-fold increase in biochemical potency and a >100-fold increase in cell-based/ replicon potency. However, BMS-605339 (5) was discontinued from clinical trials due to its cardiovascular side effects, but a new compound, BMS-890068 (6), discovered by Sun et al [26] was found to have better antiviral and pharmacokinetic properties.…”

Section: Acyl Sulfonamide P1ʹ Interaction (Bms-605339)mentioning

confidence: 99%

HCV NS3/4A Protease and its Emerging Inhibitors

Gupta¹

2017

JAPLR

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Globally, Hepatitis C virus (HCV) is a leading cause of chronic liver disease, hepatocellular carcinoma and cirrhosis and the most common reason for liver transplantation. Presently, the most common treatment for HCV infected patients is the combinations of pegylated interferon and ribavirin that provide a sustained response in patients, but its side effects are brutal. Therefore, attempts have been made to target the two important enzymes, NS3 protease and NS5B RNA polymerase, that are crucial for the replication of HCV. The article presents the development of some NS3/4A protease inhibitors that have reached the final stages of clinical trials.

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Discovery of a Potent Acyclic, Tripeptidic, Acyl Sulfonamide Inhibitor of Hepatitis C Virus NS3 Protease as a Back-up to Asunaprevir with the Potential for Once-Daily Dosing

Cited by 25 publications

References 44 publications

Avoiding Drug Resistance by Substrate Envelope-Guided Design: Toward Potent and Robust HCV NS3/4A Protease Inhibitors

Avoiding Drug Resistance by Substrate Envelope-Guided Design: Toward Potent and Robust HCV NS3/4A Protease Inhibitors

Divergent Synthesis of Cyclopropane‐Containing Lead‐Like Compounds, Fragments and Building Blocks through a Cobalt Catalyzed Cyclopropanation of Phenyl Vinyl Sulfide

HCV NS3/4A Protease and its Emerging Inhibitors

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