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

24 Citations (Scopus)

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

Fingerprint

HIV-1
Rats
Assays
Substitution reactions
Oxadiazoles
Tropics
Pharmacokinetics
Viruses
Cell culture
Permeability
Cell Culture Techniques
Ligands
Membranes
indole
In Vitro Techniques
Lead
benzamide

Keywords

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

ASJC Scopus subject areas

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

Cite this

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. / 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.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 23, No. 1, 01.01.2013, p. 203-208.

Research output: Contribution to journalArticle

Yeung, KS, Qiu, Z, Yin, Z, Trehan, A, Fang, H, Pearce, B, Yang, Z, Zadjura, L, D'Arienzo, CJ, Riccardi, K, Shi, P-Y, Spicer, TP, Gong, YF, Browning, MR, Hansel, S, Santone, K, Barker, J, Coulter, T, Lin, PF, Meanwell, NA & Kadow, JF 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, vol. 23, no. 1, pp. 203-208. https://doi.org/10.1016/j.bmcl.2012.10.117
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. / 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. In: Bioorganic and Medicinal Chemistry Letters. 2013 ; Vol. 23, No. 1. pp. 203-208.
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AU - Fang, Haiquan

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AU - Lin, Ping Fang

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