Discovery of BMS-961955, an allosteric inhibitor of the hepatitis C virus NS5B polymerase

Barbara Zhizhen Zheng; Stanley V D'Andrea; Umesh Hanumegowda; Jay O Knipe; Kathy Mosure; Xiaoliang Zhuo; Julie A Lemm; Mengping Liu; Karen L Rigat; Ying-Kai Wang; Hua Fang; Chris Poronsky; Jingfang Cutrone; Dauh-Rurng Wu; Pirama Nayagam Arunachalam; T J Balapragalathan; Arunachalam Arumugam; Arvind Mathur; Nicholas A Meanwell; Min Gao; Susan B Roberts; John F Kadow

doi:10.1016/j.bmcl.2017.06.024

Discovery of BMS-961955, an allosteric inhibitor of the hepatitis C virus NS5B polymerase

Bioorg Med Chem Lett. 2017 Aug 1;27(15):3294-3300. doi: 10.1016/j.bmcl.2017.06.024. Epub 2017 Jun 11.

Authors

Barbara Zhizhen Zheng¹, Stanley V D'Andrea², Umesh Hanumegowda³, Jay O Knipe³, Kathy Mosure³, Xiaoliang Zhuo³, Julie A Lemm⁴, Mengping Liu⁴, Karen L Rigat⁴, Ying-Kai Wang⁵, Hua Fang⁵, Chris Poronsky³, Jingfang Cutrone³, Dauh-Rurng Wu⁶, Pirama Nayagam Arunachalam⁷, T J Balapragalathan⁷, Arunachalam Arumugam⁷, Arvind Mathur⁶, Nicholas A Meanwell², Min Gao⁴, Susan B Roberts⁴, John F Kadow²

Affiliations

¹ Department of Discovery Chemistry and Molecular Technologies, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States. Electronic address: zhizhenZheng@bms.com.
² Department of Discovery Chemistry and Molecular Technologies, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
³ Department of Preclinical Candidate Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
⁴ Department of Virology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
⁵ Department of Lead Evaluation, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
⁶ Department of Discovery Synthesis, Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543, United States.
⁷ Biocon Bristol-Myers Squibb R&D Center, Biocon Park, Bommasandra IV phase, Jigani Link Road, Bengaluru 560099, India.

PMID: 28633899
DOI: 10.1016/j.bmcl.2017.06.024

Abstract

The synthesis, structure-activity relationship (SAR) data, and further optimization of the metabolic stability and pharmacokinetic (PK) properties for a previously disclosed class of cyclopropyl-fused indolobenzazepine HCV NS5B polymerase inhibitors are described. These efforts led to the discovery of BMS-961955 as a viable contingency backup to beclabuvir which was recently approved in Japan for the treatment of HCV as part of a three drug, single pill combination marketed as Ximency^TM.

Keywords: Antiviral agent; Cyclopropyl-fused indolobenzazepine; Direct-acting antiviral agent; HCV NS5B; Metabolic stability; Polymerase.

MeSH terms

Animals
Antiviral Agents / chemistry*
Antiviral Agents / pharmacokinetics
Antiviral Agents / pharmacology*
Benzazepines / chemistry*
Benzazepines / pharmacokinetics
Benzazepines / pharmacology*
Dogs
Haplorhini
Hepacivirus / drug effects*
Hepacivirus / enzymology
Hepacivirus / metabolism
Hepatitis C / drug therapy*
Hepatitis C / virology
Humans
RNA-Dependent RNA Polymerase / antagonists & inhibitors
RNA-Dependent RNA Polymerase / metabolism
Rats
Viral Nonstructural Proteins / antagonists & inhibitors*
Viral Nonstructural Proteins / metabolism

Substances

Antiviral Agents
Benzazepines
Viral Nonstructural Proteins
NS-5 protein, hepatitis C virus
RNA-Dependent RNA Polymerase