7D5L

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

Summary for 7D5L

• Entry DOI: 10.2210/pdb7d5l/pdb
• Descriptor: NS3/4A Protease, ZINC ION, [1,1,1-tris(fluoranyl)-2-methyl-propan-2-yl] ~{N}-[(1~{S},4~{R},6~{S},7~{Z},11~{R},13~{R},14~{S},18~{R})-13-ethyl-18-(7-fluoranyl-6-methoxy-isoquinolin-1-yl)oxy-11-methyl-4-[(1-methylcyclopropyl)sulfonylcarbamoyl]-2,15-bis(oxidanylidene)-3,16-diazatricyclo[14.3.0.0^{4,6}]nonadec-7-en-14-yl]carbamate, ... (4 entities in total)
• Functional Keywords: ns3/4a protease, viral protein
• Biological source: Hepacivirus C
• Total number of polymer chains: 4
• Total formula weight: 96722.58

Authors

Ghosh, K.,Anumula, R.,Kumar, A. (deposition date: 2020-09-26, release date: 2020-12-16, Last modification date: 2024-03-27)

Primary citation

Sun, L.Q.,Mull, E.,D'Andrea, S.,Zheng, B.,Hiebert, S.,Gillis, E.,Bowsher, M.,Kandhasamy, S.,Baratam, V.R.,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, Y.K.,Fang, H.,Mathur, A.,Rampulla, R.,Zvyaga, T.A.,Mosure, K.,Jenkins, S.,Falk, P.,Tagore, D.M.,Chen, C.,Rendunchintala, K.,Loy, J.,Meanwell, N.A.,McPhee, F.,Scola, P.M.
Discovery of BMS-986144, a Third-Generation, Pan-Genotype NS3/4A Protease Inhibitor for the Treatment of Hepatitis C Virus Infection.
J.Med.Chem., 63:14740-14760, 2020

PubMed 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 is functionalized with alkyl substituents, which are shown to effectively modulate both potency and absorption, distribution, metabolism, and excretion (ADME) properties. The CFBoc-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-CDO substitution pattern of the P2* isoquinoline heterocycle of was essential to securing the targeted potency, pharmacokinetic (PK), and toxicological profiles. The C6-CDO redirected metabolism away from a problematic pathway, thereby circumventing the time-dependent cytochrome P (CYP) 450 inhibition observed with the C6-CHO prototype.

PubMed: 33226226
DOI: 10.1021/acs.jmedchem.0c01296

Experimental method

X-RAY DIFFRACTION (2.15 Å)