Discovery of (7R)-14-Cyclohexyl-7-{[2-(dimethylamino)ethyl](methyl) amino}-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic Acid (MK-3281), a Potent and Orally Bioavailable Finger-Loop Inhibitor of the Hepatitis C Virus NS5B Polymerase

Citations Over TimeTop 10% of 2010 papers

Abstract

Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The polymerase of HCV is responsible for the replication of viral genome and has been a prime target for drug discovery efforts. Here, we report on the further development of tetracyclic indole inhibitors, binding to an allosteric site on the thumb domain. Structure-activity relationship (SAR) studies around an indolo-benzoxazocine scaffold led to the identification of compound 33 (MK-3281), an inhibitor with good potency in the HCV subgenomic replication assay and attractive molecular properties suitable for a clinical candidate. The compound caused a consistent decrease in viremia in vivo using the chimeric mouse model of HCV infection.

Related Papers

• → Discovery and structure–activity relationship of 2,6-disubstituted pyrazines, potent and selective inhibitors of protein kinase CK2(2012)20 cited
• → Structure activity relationship and optimization of N-(3-(2-aminothiazol-4-yl)aryl)benzenesulfonamides as anti-cancer compounds against sensitive and resistant cells(2017)15 cited
• → Peptidic HIV integrase inhibitors derived from HIV gene products: Structure–activity relationship studies(2010)22 cited
• → Discovery of benzhydrylpiperazine derivatives as CB1 receptor inverse agonists via privileged structure-based approach(2009)20 cited
• → Synthesis and SAR studies of a novel class of S1P1 receptor antagonists(2007)14 cited