Discovery of GS-9669, a Thumb Site II Non-Nucleoside Inhibitor of NS5B for the Treatment of Genotype 1 Chronic Hepatitis C Infection

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• 作者：Scott E. Lazerwith ; 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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：March 13, 2014
• 年：2014
• 卷：57
• 期：5
• 页码：1893-1901
• 全文大小：513K
• 年卷期：v.57,no.5(March 13, 2014)
• ISSN：1520-4804

文摘

Investigation of thiophene-2-carboxylic acid HCV NS5B site II inhibitors, guided by measurement of cell culture medium binding, revealed the structure鈥揳ctivity 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.