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

• Published in: MedChemComm Vol. 2; no. 11; pp. 1093 - 1098
• Main Authors: He, Gong-Xing, Yang, Zheng-Yu, Williams, Matthew, Callebaut, Christian, Cihlar, Tomas, Murray, Bernard P., Yang, Chris, Mitchell, Michael L., Liu, Hongtao, Wang, Jianying, Arimilli, Murty, Eisenberg, Eugene, Stray, Kirsten M., Tsai, Luong K., Hatada, Marcos, Chen, Xiaowu, Chen, James M., Wang, Yujin, Lee, Melody S., Strickley, Robert G., Iwata, Quynh, Zheng, Xubin, Kim, Choung U., Swaminathan, Swami, Desai, Manoj C., Lee, William A., Xu, Lianhong
• Format: Journal Article
• Language: English
• Published: 01.11.2011
• Subjects: Human immunodeficiency virus 1
• ISSN: 2040-2503; 2040-2511
• DOI: 10.1039/c1md00147g

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.