2. Academic Validation
  3. Discovery of BMS-961955, an allosteric inhibitor of the hepatitis C virus NS5B polymerase

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.
Barbara Zhizhen Zheng 1,  Stanley V D'Andrea 2,  Umesh Hanumegowda 3,  Jay O Knipe 3,  Kathy Mosure 3,  Xiaoliang Zhuo 3,  Julie A Lemm 4,  Mengping Liu 4,  Karen L Rigat 4,  Ying-Kai Wang 5,  Hua Fang 5,  Chris Poronsky 3,  Jingfang Cutrone 3,  Dauh-Rurng Wu 6,  Pirama Nayagam Arunachalam 7,  T J Balapragalathan 7,  Arunachalam Arumugam 7,  Arvind Mathur 6,  Nicholas A Meanwell 2,  Min Gao 4,  Susan B Roberts 4,  John F Kadow 2
Affiliations

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 XimencyTM.

Keywords

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

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