Discovery of 4-Benzoyl-1-[(4-methoxy-1H- pyrrolo[2,3-b]pyridin-3-yl)oxoacetyl]-2- (R)-methylpiperazine (BMS-378806):  A Novel HIV-1 Attachment Inhibitor That Interferes with CD4-gp120 Interactions

• Published in: Journal of medicinal chemistry 2003-09, Vol.46 (20), p.4236-4239
• Main Authors: Wang, Tao, Zhang, Zhongxing, Wallace, Owen B, Deshpande, Milind, Fang, Haiquan, Yang, Zheng, Zadjura, Lisa M, Tweedie, Donald L, Huang, Stella, Zhao, Fang, Ranadive, Sunanda, Robinson, Brett S, Gong, Yi-Fei, Ricarrdi, Keith, Spicer, Timothy P, Deminie, Carol, Rose, Ronald, Wang, Hwei-Gene Heidi, Blair, Wade S, Shi, Pei-Yong, Lin, Pin-fang, Colonno, Richard J, Meanwell, Nicholas A
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Anti-HIV Agents - pharmacokinetics; Anti-HIV Agents - pharmacology; Biological Availability; CCR5 Receptor Antagonists; CD4 Antigens - metabolism; Dogs; HIV Envelope Protein gp120 - metabolism; HIV-1 - drug effects; HIV-1 - metabolism; Humans; Indoles - chemistry; Indoles - pharmacokinetics; Indoles - pharmacology; Infusions, Intravenous; Macaca fascicularis; Piperazines - chemistry; Piperazines - pharmacokinetics; Piperazines - pharmacology; Rats; Receptors, CXCR4 - antagonists & inhibitors
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm034082o

Indole derivative 1 interferes with the interaction of the HIV surface protein gp120 with the host cell receptor CD4. The 4-fluoro derivative 2 exhibited markedly enhanced potency and was bioavailable in the rat, dog, and cynomolgus monkey when administered orally as a solution formulation. However, aqueous suspensions of 2 were poorly bioavailable, indicative of dissolution-limited absorption. The 7-azaindole derivative 3, BMS-378806, exhibited improved pharmaceutical properties while retaining the HIV-1 inhibitory profile of 2.