Discovery of GS-9669, a thumb site II non-nucleoside inhibitor of NS5B for the treatment of genotype 1 chronic hepatitis C infection

J Med Chem. 2014 Mar 13;57(5):1893-901. doi: 10.1021/jm401420j.

Scott E Lazerwith ¹, Willard Lew, Jennifer Zhang, Philip Morganelli, Qi Liu, Eda Canales, Michael O Clarke, Edward Doerffler, Daniel Byun, Michael Mertzman, Hong Ye, Lee Chong, Lianhong Xu, Todd Appleby, Xiaowu Chen, Martijn Fenaux, Ahmad Hashash, Stephanie A Leavitt, Eric Mabery, Mike Matles, Judy W Mwangi, Yang Tian, Yu-Jen Lee, Jingyu Zhang, Christine Zhu, Bernard P Murray, William J Watkins

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Affiliation

1 Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States.

PMID: 24144213 DOI: 10.1021/jm401420j

Abstract

Investigation of thiophene-2-carboxylic acid HCV NS5B site II inhibitors, guided by measurement of Cell Culture medium binding, revealed the structure-activity relationships for intrinsic cellular potency. The pharmacokinetic profile was enhanced through incorporation of heterocyclic ethers on the N-alkyl substituent. Hydroxyl groups were incorporated to modulate protein binding. Intrinsic potency was further improved through enantiospecific introduction of an olefin in the N-acyl motif, resulting in the discovery of the phase 2 clinical candidate GS-9669. The unexpected activity of this compound against the clinically relevant NS5B M423T mutant, relative to the wild type, was shown to arise from both the N-alkyl substituent and the N-acyl group.

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