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
  • 1. Bristol-Myers Squibb Research & Development, 5 Research Parkway, PO Box 5100, Wallingford, CT 06492, USA. [email protected]
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.