Inhibitors of HIV-1 attachment. Part 8: The effect of C7-heteroaryl substitution on the potency, and in vitro and in vivo profiles of indole-based inhibitors

• Published in: Bioorganic & medicinal chemistry letters 2013-01, Vol.23 (1), p.203-208
• Main Authors: Yeung, Kap-Sun, Qiu, Zhilei, Yin, Zhiwei, Trehan, Ashok, Fang, Haiquan, Pearce, Bradley, Yang, Zheng, Zadjura, Lisa, D’Arienzo, Celia J., Riccardi, Keith, Shi, Pei-Yong, Spicer, Timothy P., Gong, Yi-Fei, Browning, Marc R., Hansel, Steven, Santone, Kenneth, Barker, Jonathan, Coulter, Thomas, Lin, Ping-Fang, Meanwell, Nicholas A., Kadow, John F.
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacokinetics; Caco-2 Cells; cell culture; Cell Membrane Permeability - drug effects; Half-Life; Heterocycles; HIV-1 - drug effects; HIV-1 - metabolism; HIV-1 attachment inhibitors; Human immunodeficiency virus 1; Humans; Indole glyoxamide; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacokinetics; Ligand efficiency; Lipophilic ligand efficiency; membrane permeability; Microsomes, Liver - metabolism; oral exposure; pharmacokinetics; Rats; Structure-Activity Relationship; Virus Attachment - drug effects; viruses
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.10.117

Optimization of the early lead compound 2 with heteroaryl substitution at the C7 position identified inhibitors with picomolar inhibitory activity. These C7-heteroaryl-indole analogs maintained the ligand efficiency (LE) of 2 and were also lipophilic efficient as measured by LLE and LELP. The highly permeable 1,2,4-oxadiazole analog 13 exhibited the highest oral exposure in rats. As part of the SAR profiling of the indole-oxoacetic piperazinyl benzamide class of HIV-1 attachment inhibitors, substitution at the C7 position of the lead 4-fluoroindole 2 with various 5- and 6-membered heteroaryl moieties was explored. Highly potent (picomolar) inhibitors of pseudotyped HIV-1 in a primary, cell-based assay were identified and select examples were shown to possess nanomolar inhibitory activity against M- and T-tropic viruses in cell culture. These C7-heteroaryl-indole analogs maintained the ligand efficiency (LE) of 2 and were also lipophilic efficient as measured by LLE and LELP. Pharmacokinetic studies of this class of inhibitor in rats showed that several possessed substantially improved IV clearance and half-lives compared to 2. Oral exposure in the rat correlated with membrane permeability as measured in a Caco-2 assay where the highly permeable 1,2,4-oxadiazole analog 13 exhibited the highest exposure.