2. Academic Validation
  3. 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

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

  • Bioorg Med Chem Lett. 2013 Jan 1;23(1):203-8. doi: 10.1016/j.bmcl.2012.10.117.
Kap-Sun Yeung 1,  Zhilei Qiu,  Zhiwei Yin,  Ashok Trehan,  Haiquan Fang,  Bradley Pearce,  Zheng Yang,  Lisa Zadjura,  Celia J D'Arienzo,  Keith Riccardi,  Pei-Yong Shi,  Timothy P Spicer,  Yi-Fei Gong,  Marc R Browning,  Steven Hansel,  Kenneth Santone,  Jonathan Barker,  Thomas Coulter,  Ping-Fang Lin,  Nicholas A Meanwell,  John F Kadow
Affiliations

Affiliation

  • 1 Bristol-Myers Squibb Research & Development, 5 Research Parkway, PO Box 5100, Wallingford, CT 06492, USA. kapsun.yeung@bms.com
PMID: 23200249 DOI: 10.1016/j.bmcl.2012.10.117
Abstract

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.

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