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

Lazerwith, SE and Lew, W and Morganelli, P and Liu, Q and Canales, E and Clarke, MO and Doerffler, E and Byun, D and Mertzman, M and Ye, H and Chong, L and Xu, L and Appleby, T and Chen, X and Fenaux, M and Hashash, A and Leavitt, SA and Mabery, E and Matles, M and Mwangi, JW and Tian, Y and Lee, Y and Zhang, J and Zhu, C and Murray, BP and Watkins, WJ (2014) Discovery of GS-9669, a thumb site II non-nucleoside inhibitor of NS5B for the treatment of genotype 1 chronic hepatitis C infection. Journal of Medicinal Chemistry. pp. 1893-1901.


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. 2013 American Chemical Society

Item Type: Article
Additional Information: NIBR author: Fenaux, M institute: NIBR contributor address: (Lazerwith, Lew, Zhang, Morganelli, Liu, Canales, Clarke, Doerffler, Byun, Mertzman, Ye, Chong, Xu, Appleby, Chen, Fenaux, Hashash, Leavitt, Mabery, Matles, Mwangi, Tian, Lee, Zhang, Zhu, Murray, Watkins) Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, United States (Mertzman) Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, United States (Fenaux) Novartis Institutes for BioMedical Research, 4560 Horton Street, Emeryville, CA 94608, United States (Hashash) Ironwood Pharmaceuticals, 301 Binney Street, Cambridge, MA 02142, United States (Mabery) Reset Therapeutics, 863A Mitten Road, Burlingame, CA 94010., United States
Date Deposited: 13 Oct 2015 13:12
Last Modified: 13 Oct 2015 13:12


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