Syntheses and initial evaluation of a series of indolo-fused heterocyclic inhibitors of the polymerase enzyme (NS5B) of the hepatitis C virus
Xiaofan Zheng, Thomas W. Hudyma, Scott W. Martin, Carl Bergstrom, Min Ding, Feng He, Jeffrey Romine, Michael A. Poss, John F. Kadow, Chong-Hwan Chang, John Wan, Mark R. Witmerhttp://academic.research.microsoft.com/io.ashx?type=5&id=49476375&selfId1=0&selfId2=0&maxNumber=12&query=
Herein, we present initial SAR studies on a series of bridged 2-arylindole-based NS5B inhibitors. The introduction of bridging elements between the indole N1 and the ortho-position of the 2-aryl moiety resulted in conformationally constrained heterocycles that possess multiple additional vectors for further exploration. The binding mode and pharmacokinetic (PK) properties of select examples, including: 13-cyclohexyl-6-oxo-6,7-dihydro-5H-indolo[2,1-d][1,4]benzodiazepine-10-carboxylic acid (7) (IC50=0.07μM, %F=18), are reported.