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

Kap Sun Yeung, 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. MeanwellJohn F. Kadow

Research output: Contribution to journalArticle

29 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)203-208
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume23
Issue number1
DOIs
StatePublished - Jan 1 2013
Externally publishedYes

Keywords

  • HIV-1 attachment inhibitors
  • Heterocycles
  • Indole glyoxamide
  • Ligand efficiency
  • Lipophilic ligand efficiency

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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    Yeung, K. S., Qiu, Z., Yin, Z., Trehan, A., Fang, H., Pearce, B., Yang, Z., Zadjura, L., D'Arienzo, C. J., Riccardi, K., Shi, P. Y., Spicer, T. P., Gong, Y. F., Browning, M. R., Hansel, S., Santone, K., Barker, J., Coulter, T., Lin, P. F., ... Kadow, J. F. (2013). 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. Bioorganic and Medicinal Chemistry Letters, 23(1), 203-208. https://doi.org/10.1016/j.bmcl.2012.10.117