Discovery of BMS-986144, a Third-Generation, Pan-Genotype NS3/4A Protease Inhibitor for the Treatment of Hepatitis C Virus Infection.
Li-Qiang SunEric MullStanley D'AndreaBarbara Zhizhen ZhengSheldon HiebertEric GillisMichael BowsherSarkunam KandhasamyVenkata Rao BaratamSunitha PuttaswamyNagalakshmi PulicharlaSureshbabu VishwakrishnanSubba ReddyRavi TrivediSarmistha SinhaSankar SivaprasadAbhijith RaoSalil DesaiKaushik GhoshRushith AnumulaAmit KumarRamkumar RajamaniYing-Kai WangHua FangArvind MathurRichard RampullaTatyana A ZvyagaKathy MosureSusan JenkinsPaul FalkDebarati M TagoreChaoqun ChenKishore RendunchintalaJames LoyNicholas A MeanwellFiona McPheePaul M ScolaPublished in: Journal of medicinal chemistry (2020)
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.
Keyphrases
- hepatitis c virus
- hepatitis c virus infection
- small molecule
- human immunodeficiency virus
- high throughput
- cystic fibrosis
- nk cells
- molecular docking
- ionic liquid
- positron emission tomography
- cancer therapy
- room temperature
- combination therapy
- drug delivery
- hiv infected
- smoking cessation
- molecularly imprinted
- tandem mass spectrometry