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Discovery of BMS-986144, a Third-Generation, Pan-Genotype NS3/4A Protease Inhibitor for the Treatment of Hepatitis C Virus Infection.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2020 Dec 10; Vol. 63 (23), pp. 14740-14760. Date of Electronic Publication: 2020 Nov 23. - Publication Year :
- 2020
-
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 <subscript>3</subscript> 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-CD <subscript>3</subscript> O substitution pattern of the P2* isoquinoline heterocycle of 21 was essential to securing the targeted potency, pharmacokinetic (PK), and toxicological profiles. The C6-CD <subscript>3</subscript> O redirected metabolism away from a problematic pathway, thereby circumventing the time-dependent cytochrome P (CYP) 450 inhibition observed with the C6-CH <subscript>3</subscript> O prototype.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 63
- Issue :
- 23
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 33226226
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.0c01296