2. Academic Validation
  3. 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

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

  • J Med Chem. 2016 Sep 8;59(17):8042-60. doi: 10.1021/acs.jmedchem.6b00821.
Li-Qiang Sun,  Eric Mull,  Barbara Zheng,  Stanley D'Andrea,  Qian Zhao,  Alan Xiangdong Wang,  Ny Sin,  Brian L Venables,  Sing-Yuen Sit,  Yan Chen,  Jie Chen,  Anthony Cocuzza,  Donna M Bilder,  Arvind Mathur 1,  Richard Rampulla 1,  Bang-Chi Chen 1,  Theerthagiri Palani 2,  Sivakumar Ganesan 2,  Pirama Nayagam Arunachalam 2,  Paul Falk,  Steven Levine,  Chaoqun Chen,  Jacques Friborg,  Fei Yu,  Dennis Hernandez,  Amy K Sheaffer,  Jay O Knipe,  Yong-Hae Han,  Richard Schartman,  Maria Donoso,  Kathy Mosure,  Michael W Sinz,  Tatyana Zvyaga,  Ramkumar Rajamani,  Kevin Kish,  Jeffrey Tredup,  Herbert E Klei,  Qi Gao 3,  Alicia Ng 3,  Luciano Mueller,  Dennis M Grasela,  Stephen Adams 4,  James Loy,  Paul C Levesque 4,  Huabin Sun 4,  Hong Shi 4,  Lucy Sun 4,  William Warner 4,  Danshi Li 4,  Jialong Zhu 4,  Ying-Kai Wang,  Hua Fang,  Mark I Cockett,  Nicholas A Meanwell,  Fiona McPhee,  Paul M Scola
Affiliations

Affiliations

  • 1 Department of Discovery Synthesis, Bristol-Myers Squibb Research and Development , Route 206 and Provinceline Road, Princeton, New Jersey 08543, United States.
  • 2 Biocon Bristol-Myers Squibb R&D Center , Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bangalore 560099, India.
  • 3 Department of Pharmaceutical Development, Bristol-Myers Squibb Research and Development , 1 Squibb Drive, New Brunswick, New Jersey 08903, United States.
  • 4 Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States.
PMID: 27564532 DOI: 10.1021/acs.jmedchem.6b00821
Abstract

The discovery of a back-up to the hepatitis C virus NS3 protease inhibitor asunaprevir (2) is described. The objective of this work was the identification of a drug with Antiviral properties and toxicology parameters similar to 2, but with a preclinical pharmacokinetic (PK) profile that was predictive of once-daily dosing. Critical to this discovery process was the employment of an ex vivo cardiovascular (CV) model which served to identify compounds that, like 2, were free of the CV liabilities that resulted in the discontinuation of BMS-605339 (1) from clinical trials. Structure-activity relationships (SARs) at each of the structural subsites in 2 were explored with substantial improvement in PK through modifications at the P1 site, while potency gains were found with small, but rationally designed structural changes to P4. Additional modifications at P3 were required to optimize the CV profile, and these combined SARs led to the discovery of BMS-890068 (29).

Figures