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
  • 1. Department of Discovery Chemistry and Molecular Technologies, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States. Electronic address: [email protected].
  • 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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