Issue 11, 2011
From the journal:

MedChemComm

Discovery of GS-8374, a potent human immunodeficiency virus type 1 protease inhibitor with a superior resistance profile†

Gong-Xing He,a   Zheng-Yu Yang,a   Matthew Williams,‡a   Christian Callebaut,b   Tomas Cihlar,b   Bernard P. Murray,c   Chris Yang,c   Michael L. Mitchell,a   Hongtao Liu,a   Jianying Wang,‡a   Murty Arimilli,‡a   Eugene Eisenberg,c   Kirsten M. Stray,b   Luong K. Tsai,b   Marcos Hatada,‡d   Xiaowu Chen,d   James M. Chen,‡d   Yujin Wang,c   Melody S. Lee,‡c   Robert G. Strickley,e   Quynh Iwata,e   Xubin Zheng,c   Choung U. Kim,a   Swami Swaminathan,d   Manoj C. Desai,a   William A. Leef  and  Lianhong Xu*a  

* Corresponding authors

a Department of Medicinal Chemistry, Gilead Sciences Inc, 333 Lakeside Drive, Foster City, CA, USA
E-mail: lianhong.xu@gilead.com.

b Department of Biology, Gilead Sciences Inc, 333 Lakeside Drive, Foster City, CA, USA

c Department of Drug Metabolism, Gilead Sciences Inc, 333 Lakeside Drive, Foster City, CA, USA

d Department of Structural Chemistry, Gilead Sciences Inc, 333 Lakeside Drive, Foster City, CA, USA

e Department of Formulation, Gilead Sciences Inc, 333 Lakeside Drive, Foster City, CA, USA

f Gilead Research, Gilead Sciences Inc, 333 Lakeside Drive, Foster City, CA, USA

Abstract

Introduction of a unique phosphonate moiety at the P1 position of the TMC-126 (3) scaffold provided a series of novel HIV-1 protease inhibitors (PIs) with an improved resistance profile against highly resistant variants. Optimization of the linker and phosphonate moieties lead to the identification of GS-8374 (1). Compound 1 is a potent and orally bioavailable HIV-1 PI with a superior resistance profile. Synthesis and characterization of 1 are reported.

Graphical abstract: Discovery of GS-8374, a potent human immunodeficiency virus type 1 protease inhibitor with a superior resistance profile

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Article information

DOI
https://doi.org/10.1039/C1MD00147G
Article type
Concise Article
Submitted
11 Jun 2011
Accepted
19 Jul 2011
First published
07 Sep 2011

Med. Chem. Commun., 2011,2, 1093-1098

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Discovery of GS-8374, a potent human immunodeficiency virus type 1 protease inhibitor with a superior resistance profile

G. He, Z. Yang, M. Williams, C. Callebaut, T. Cihlar, B. P. Murray, C. Yang, M. L. Mitchell, H. Liu, J. Wang, M. Arimilli, E. Eisenberg, K. M. Stray, L. K. Tsai, M. Hatada, X. Chen, J. M. Chen, Y. Wang, M. S. Lee, R. G. Strickley, Q. Iwata, X. Zheng, C. U. Kim, S. Swaminathan, M. C. Desai, W. A. Lee and L. Xu, Med. Chem. Commun., 2011, 2, 1093 DOI: 10.1039/C1MD00147G

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