1431285-71-0Relevant articles and documents
Hepatitis C replication inhibitors that target the viral NS4B protein
Miller, John F.,Chong, Pek Y.,Shotwell, J. Brad,Catalano, John G.,Tai, Vincent W.-F.,Fang, Jing,Banka, Anna L.,Roberts, Christopher D.,Youngman, Michael,Zhang, Huichang,Xiong, Zhiping,Mathis, Amanda,Pouliot, Jeffery J.,Hamatake, Robert K.,Price, Daniel J.,Seal, John W.,Stroup, Lisa L.,Creech, Katrina L.,Carballo, Luz H.,Todd, Dan,Spaltenstein, Andrew,Furst, Sylvia,Hong, Zhi,Peat, Andrew J.
, p. 2107 - 2120 (2014)
We describe the preclinical development and in vivo efficacy of a novel chemical series that inhibits hepatitis C virus replication via direct interaction with the viral nonstructural protein 4B (NS4B). Significant potency improvements were realized through isosteric modifications to our initial lead 1a. The temptation to improve antiviral activity while compromising physicochemical properties was tempered by the judicial use of ligand efficiency indices during lead optimization. In this manner, compound 1a was transformed into (+)-28a which possessed an improved antiviral profile with no increase in molecular weight and only a modest elevation in lipophilicity. Additionally, we employed a chimeric "humanized" mouse model of HCV infection to demonstrate for the first time that a small molecule with high in vitro affinity for NS4B can inhibit viral replication in vivo. This successful proof-of-concept study suggests that drugs targeting NS4B may represent a viable treatment option for curing HCV infection.
Design and synthesis of spirocyclic compounds as HCV replication inhibitors by targeting viral NS4B protein
Tai, Vincent W.-F.,Garrido, Dulce,Price, Daniel J.,Maynard, Andrew,Pouliot, Jeffrey J.,Xiong, Zhiping,Seal, John W.,Creech, Katrina L.,Kryn, Luz H.,Baughman, Todd M.,Peat, Andrew J.
, p. 2288 - 2294 (2014/05/20)
Two novel series of spirocyclic piperidine analogs appended to a pyrazolo[1,5-a]pyridine core were designed, synthesized and evaluated for their anti-HCV activity. A series of piperidine ketals afforded dispiro 6p which showed excellent in vitro anti-HCV activities (EC50 of 1.5 nM and 1.2 nM against genotype 1a and 1b replicons, respectively). A series of piperidine oxazolidinones afforded 27c which showed EC50's of 10.9 nM and 6.1 nM against 1a and 1b replicons, respectively. Both compounds 6p and 27c bound directly to non-structural NS4B protein in vitro (IC50's = 10.2 and 30.4 nM, respectively) and exhibited reduced potency in replicons containing resistance mutations encoding changes in the NS4B protein.
