Discovery of a Hepatitis C Virus NS5B Replicase Palm Site Allosteric Inhibitor (BMS-929075) Advanced to Phase 1 Clinical Studies

  • J Med Chem. 2017 May 25;60(10):4369-4385. doi: 10.1021/acs.jmedchem.7b00328.
Kap-Sun Yeung  1 ,  Brett R Beno  1 ,  Kyle Parcella  1 ,  John A Bender  1 ,  Katherine A Grant-Young  1 ,  Andrew Nickel  1 ,  Prashantha Gunaga  2 ,  Prakash Anjanappa  2 ,  Rajesh Onkardas Bora  2 ,  Kumaravel Selvakumar  2 ,  Karen Rigat  1 ,  Ying-Kai Wang  1 ,  Mengping Liu  1 ,  Julie Lemm  1 ,  Kathy Mosure  1 ,  Steven Sheriff  3 ,  Changhong Wan  3 ,  Mark Witmer  3 ,  Kevin Kish  3 ,  Umesh Hanumegowda  1 ,  Xiaoliang Zhuo  1 ,  Yue-Zhong Shu  3 ,  Dawn Parker  1 ,  Roy Haskell  1 ,  Alicia Ng  3 ,  Qi Gao  4 ,  Elizabeth Colston  3 ,  Joseph Raybon  3 ,  Dennis M Grasela  3 ,  Kenneth Santone  1 ,  Min Gao  1 ,  Nicholas A Meanwell  1 ,  Michael Sinz  1 ,  Matthew G Soars  1 ,  Jay O Knipe  1 ,  Susan B Roberts  1 ,  John F Kadow  1
Affiliations
  • 1. Bristol-Myers Squibb Research and Development , P.O. Box 5100, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
  • 2. Department of Discovery Chemistry, Biocon Bristol-Myers Squibb Research and Development Center , Biocon Park, Jigani Link Road, Bommasandra IV, Bangalore 560099, India.
  • 3. Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton, New Jersey 08543, United States.
  • 4. Bristol-Myers Squibb Research and Development , 1 Squibb Drive, New Brunswick, New Jersey 08901, United States.
PMID: 28430437 DOI: 10.1021/acs.jmedchem.7b00328
Abstract

The hepatitis C virus (HCV) NS5B replicase is a prime target for the development of direct-acting Antiviral drugs for the treatment of chronic HCV Infection. Inspired by the overlay of bound structures of three structurally distinct NS5B palm site allosteric inhibitors, the high-throughput screening hit anthranilic acid 4, the known benzofuran analogue 5, and the benzothiadiazine derivative 6, an optimization process utilizing the simple benzofuran template 7 as a starting point for a fragment growing approach was pursued. A delicate balance of molecular properties achieved via disciplined lipophilicity changes was essential to achieve both high affinity binding and a stringent targeted absorption, distribution, metabolism, and excretion profile. These efforts led to the discovery of BMS-929075 (37), which maintained ligand efficiency relative to early leads, demonstrated efficacy in a triple combination regimen in HCV replicon cells, and exhibited consistently high oral bioavailability and pharmacokinetic parameters across preclinical animal species. The human PK properties from the Phase I clinical studies of 37 were better than anticipated and suggest promising potential for QD administration.

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