Discovery of BMS-986144, a Third-Generation, Pan-Genotype NS3/4A Protease Inhibitor for the Treatment of Hepatitis C Virus Infection

  • J Med Chem. 2020 Dec 10;63(23):14740-14760. doi: 10.1021/acs.jmedchem.0c01296.
Li-Qiang Sun  1 ,  Eric Mull  2 ,  Stanley D'Andrea  2 ,  Barbara Zheng  1 ,  Sheldon Hiebert  2 ,  Eric Gillis  2 ,  Michael Bowsher  2 ,  Sarkunam Kandhasamy  3 ,  Venkata Rao Baratam  3 ,  Sunitha Puttaswamy  3 ,  Nagalakshmi Pulicharla  3 ,  Sureshbabu Vishwakrishnan  3 ,  Subba Reddy  3 ,  Ravi Trivedi  3 ,  Sarmistha Sinha  3 ,  Sankar Sivaprasad  3 ,  Abhijith Rao  3 ,  Salil Desai  3 ,  Kaushik Ghosh  3 ,  Rushith Anumula  3 ,  Amit Kumar  3 ,  Ramkumar Rajamani  4 ,  Ying-Kai Wang  1 ,  Hua Fang  2 ,  Arvind Mathur  2 ,  Richard Rampulla  2 ,  Tatyana A Zvyaga  2 ,  Kathy Mosure  4 ,  Susan Jenkins  2 ,  Paul Falk  2 ,  Debarati M Tagore  3 ,  Chaoqun Chen  2 ,  Kishore Rendunchintala  3 ,  James Loy  4 ,  Nicholas A Meanwell  1 ,  Fiona McPhee  4 ,  Paul M Scola  4
Affiliations
  • 1. Bristol Myers Squibb Research and Early Development, Route 206 & Province Line Road, Princeton, New Jersey 08543, United States.
  • 2. Bristol Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
  • 3. Biocon-Bristol Myers Squibb Research and Development Center, Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bangalore 560099, India.
  • 4. Bristol Myers Squibb Research and Early Development, 100 Binney Street, Cambridge, Massachusetts 02142, United States.
PMID: 33226226 DOI: 10.1021/acs.jmedchem.0c01296
Abstract

The discovery of a pan-genotypic hepatitis C virus (HCV) NS3/4A protease inhibitor based on a P1-P3 macrocyclic tripeptide motif is described. The all-carbon tether linking the P1-P3 subsites of 21 is functionalized with alkyl substituents, which are shown to effectively modulate both potency and absorption, distribution, metabolism, and excretion (ADME) properties. The CF3Boc-group that caps the P3 amino moiety was discovered to be an essential contributor to metabolic stability, while positioning a methyl group at the C1 position of the P1' cyclopropyl ring enhanced plasma trough values following oral administration to rats. The C7-fluoro, C6-CD3O substitution pattern of the P2* isoquinoline heterocycle of 21 was essential to securing the targeted potency, pharmacokinetic (PK), and toxicological profiles. The C6-CD3O redirected metabolism away from a problematic pathway, thereby circumventing the time-dependent cytochrome P (CYP) 450 inhibition observed with the C6-CH3O prototype.