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. Meanwell; John F. Kadow

doi:10.1016/j.bmcl.2012.10.117

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

Biochemistry & Molecular Biology

Research output: Contribution to journal › Article › peer-review

40 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 language	English (US)
Pages (from-to)	203-208
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	23
Issue number	1
DOIs	https://doi.org/10.1016/j.bmcl.2012.10.117
State	Published - Jan 1 2013

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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10.1016/j.bmcl.2012.10.117

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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

Yeung, KS, Qiu, Z, Yin, Z, Trehan, A, Fang, H, Pearce, B, Yang, Z, Zadjura, L, D'Arienzo, CJ, Riccardi, K, Shi, PY, 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

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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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AU - Qiu, Zhilei

AU - Yin, Zhiwei

AU - Trehan, Ashok

AU - Fang, Haiquan

AU - Pearce, Bradley

AU - Yang, Zheng

AU - Zadjura, Lisa

AU - D'Arienzo, Celia J.

AU - Riccardi, Keith

AU - Shi, Pei Yong

AU - Spicer, Timothy P.

AU - Gong, Yi Fei

AU - Browning, Marc R.

AU - Hansel, Steven

AU - Santone, Kenneth

AU - Barker, Jonathan

AU - Coulter, Thomas

AU - Lin, Ping Fang

AU - Meanwell, Nicholas A.

AU - Kadow, John F.

PY - 2013/1/1

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AB - 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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KW - Ligand efficiency

KW - Lipophilic ligand efficiency

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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

Abstract

Keywords

ASJC Scopus subject areas

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