Inhibitors of HIV-1 attachment. Part 7: Indole-7-carboxamides as potent and orally bioavailable antiviral agents

• Published in: Bioorganic & medicinal chemistry letters 2013-01, Vol.23 (1), p.198-202
• Main Authors: Yeung, Kap-Sun, Qiu, Zhilei, Xue, Quifen, Fang, Haiquan, Yang, Zheng, Zadjura, Lisa, D’Arienzo, Celia J., Eggers, Betsy J., Riccardi, Keith, Shi, Pei-Yong, Gong, Yi-Fei, Browning, Marc R., Gao, Qi, Hansel, Steven, Santone, Kenneth, Lin, Ping-Fang, Meanwell, Nicholas A., Kadow, John F.
• Format: Article
• Language: English
• Subjects: Amides; Amides - chemical synthesis; Amides - chemistry; Amides - pharmacokinetics; Animals; Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacokinetics; antiviral agents; Antivirals; Biological Availability; Caco-2 Cells; Cell Membrane Permeability - drug effects; chemistry; Crystallography, X-Ray; Dogs; Half-Life; Haplorhini; HIV-1 - drug effects; HIV-1 - metabolism; HIV-1 attachment inhibitors; Human immunodeficiency virus 1; Humans; Indole glyoxamide; Indoles - chemistry; membrane permeability; Microsomes, Liver - metabolism; Molecular Conformation; pharmacokinetics; Rats; Structure-Activity Relationship; Virus Attachment - drug effects; viruses
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.10.115

Optimization of the early lead compound 1 with various carboxamide substitution at the C7 position provided heteroaryl carboxamide analogs (e.g., 35) that exhibited picomolar potency, while the simple methyl amide analog 4 displayed a promising in vitro profile and favorable pharmacokinetic properties in preclinical species. A series of substituted carboxamides at the indole C7 position of the previously described 4-fluoro-substituted indole HIV-1 attachment inhibitor 1 was synthesized and the SAR delineated. Heteroaryl carboxamide inhibitors that exhibited pM potency in the primary cell-based assay against a pseudotype virus expressing a JRFL envelope were identified. The simple methyl amide analog 4 displayed a promising in vitro profile, with its favorable HLM stability and membrane permeability translating into favorable pharmacokinetic properties in preclinical species.