1. Discovery of BMS-986144, a Third-Generation, Pan-Genotype NS3/4A Protease Inhibitor for the Treatment of Hepatitis C Virus Infection.
- Author
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Sun LQ, Mull E, D'Andrea S, Zheng B, Hiebert S, Gillis E, Bowsher M, Kandhasamy S, Baratam VR, Puttaswamy S, Pulicharla N, Vishwakrishnan S, Reddy S, Trivedi R, Sinha S, Sivaprasad S, Rao A, Desai S, Ghosh K, Anumula R, Kumar A, Rajamani R, Wang YK, Fang H, Mathur A, Rampulla R, Zvyaga TA, Mosure K, Jenkins S, Falk P, Tagore DM, Chen C, Rendunchintala K, Loy J, Meanwell NA, McPhee F, and Scola PM
- Subjects
- Animals, Antiviral Agents chemical synthesis, Antiviral Agents metabolism, Antiviral Agents pharmacokinetics, CHO Cells, Cricetulus, Drug Discovery, Drug Stability, Hepacivirus drug effects, Hepacivirus enzymology, Microbial Sensitivity Tests, Microsomes, Liver metabolism, Molecular Structure, Peptides, Cyclic chemical synthesis, Peptides, Cyclic metabolism, Peptides, Cyclic pharmacokinetics, Rats, Serine Proteinase Inhibitors chemical synthesis, Serine Proteinase Inhibitors metabolism, Serine Proteinase Inhibitors pharmacokinetics, Structure-Activity Relationship, Antiviral Agents pharmacology, Peptides, Cyclic pharmacology, Serine Proteinase Inhibitors pharmacology, Viral Nonstructural Proteins antagonists & inhibitors
- 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 CF
3 Boc-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-CD3 O substitution pattern of the P2* isoquinoline heterocycle of 21 was essential to securing the targeted potency, pharmacokinetic (PK), and toxicological profiles. The C6-CD3 O redirected metabolism away from a problematic pathway, thereby circumventing the time-dependent cytochrome P (CYP) 450 inhibition observed with the C6-CH3 O prototype.- Published
- 2020
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