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
Affiliations
  • 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.