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

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• 作者：Kap-Sun Yeung^a ; ^{kapsun.yeung@bms.com} ; Zhilei Qiu^a ; Zhiwei Yin^a ; Ashok Trehan^a ; Haiquan Fang^a ; Bradley Pearce^a ; Zheng Yang^a ; Lisa Zadjura^a ; Celia J. D&#8217 ; Arienzo^a ; Keith Riccardi^a ; Pei-Yong Shi^a ; Timothy P. Spicer^a ; Yi-Fei Gong^a ; Marc R. Browning^a ; Steven Hansel^a ; Kenneth Santone^a ; Jonathan Barker^b ; Thomas Coulter^b ; Ping-Fang Lin^a ; Nicholas A. Meanwell^a ; John F. Kadow^a
• 关键词：HIV-1 attachment inhibitors ; Indole glyoxamide ; Heterocycles ; Ligand efficiency ; Lipophilic ligand efficiency
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2013
• 出版时间：1 January, 2013
• 年：2013
• 卷：23
• 期：1
• 页码：203-208
• 全文大小：3596 K

文摘

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 boldFont"">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 boldFont"">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 boldFont"">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 boldFont"">13 exhibited the highest exposure.