Inhibitors of HIV-1 attachment. Part 7: Indole-7-carboxamides as potent and orally bioavailable antiviral agents

Kap Sun Yeung; Zhilei Qiu; Quifen Xue; Haiquan Fang; Zheng Yang; Lisa Zadjura; Celia J. D'Arienzo; Betsy J. Eggers; Keith Riccardi; Pei Yong Shi; Yi Fei Gong; Marc R. Browning; Qi Gao; Steven Hansel; Kenneth Santone; Ping Fang Lin; Nicholas A. Meanwell; John F. Kadow

doi:10.1016/j.bmcl.2012.10.115

Inhibitors of HIV-1 attachment. Part 7: Indole-7-carboxamides as potent and orally bioavailable antiviral agents

Kap Sun Yeung, Zhilei Qiu, Quifen Xue, Haiquan Fang, Zheng Yang, Lisa Zadjura, Celia J. D'Arienzo, Betsy J. Eggers, Keith Riccardi, Pei Yong Shi, Yi Fei Gong, Marc R. Browning, Qi Gao, Steven Hansel, Kenneth Santone, Ping Fang Lin, Nicholas A. Meanwell, John F. Kadow

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

37 Scopus citations

Abstract

A series of substituted carboxamides at the indole C7 position of the previously described 4-fluoro-substituted indole HIV-1 attachment inhibitor 1 was synthesized and the SAR delineated. Heteroaryl carboxamide inhibitors that exhibited pM potency in the primary cell-based assay against a pseudotype virus expressing a JRFL envelope were identified. The simple methyl amide analog 4 displayed a promising in vitro profile, with its favorable HLM stability and membrane permeability translating into favorable pharmacokinetic properties in preclinical species.

Original language	English (US)
Pages (from-to)	198-202
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	23
Issue number	1
DOIs	https://doi.org/10.1016/j.bmcl.2012.10.115
State	Published - Jan 1 2013
Externally published	Yes

Keywords

Amides
Antivirals
HIV-1 attachment inhibitors
Indole glyoxamide
Molecular conformation

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.2012.10.115

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Yeung, K. S., Qiu, Z., Xue, Q., Fang, H., Yang, Z., Zadjura, L., D'Arienzo, C. J., Eggers, B. J., Riccardi, K., Shi, P. Y., Gong, Y. F., Browning, M. R., Gao, Q., Hansel, S., Santone, K., Lin, P. F., Meanwell, N. A., & Kadow, J. F. (2013). Inhibitors of HIV-1 attachment. Part 7: Indole-7-carboxamides as potent and orally bioavailable antiviral agents. Bioorganic and Medicinal Chemistry Letters, 23(1), 198-202. https://doi.org/10.1016/j.bmcl.2012.10.115

Yeung, KS, Qiu, Z, Xue, Q, Fang, H, Yang, Z, Zadjura, L, D'Arienzo, CJ, Eggers, BJ, Riccardi, K, Shi, PY, Gong, YF, Browning, MR, Gao, Q, Hansel, S, Santone, K, Lin, PF, Meanwell, NA & Kadow, JF 2013, 'Inhibitors of HIV-1 attachment. Part 7: Indole-7-carboxamides as potent and orally bioavailable antiviral agents', Bioorganic and Medicinal Chemistry Letters, vol. 23, no. 1, pp. 198-202. https://doi.org/10.1016/j.bmcl.2012.10.115

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abstract = "A series of substituted carboxamides at the indole C7 position of the previously described 4-fluoro-substituted indole HIV-1 attachment inhibitor 1 was synthesized and the SAR delineated. Heteroaryl carboxamide inhibitors that exhibited pM potency in the primary cell-based assay against a pseudotype virus expressing a JRFL envelope were identified. The simple methyl amide analog 4 displayed a promising in vitro profile, with its favorable HLM stability and membrane permeability translating into favorable pharmacokinetic properties in preclinical species.",

keywords = "Amides, Antivirals, HIV-1 attachment inhibitors, Indole glyoxamide, Molecular conformation",

author = "Yeung, {Kap Sun} and Zhilei Qiu and Quifen Xue and Haiquan Fang and Zheng Yang and Lisa Zadjura and D'Arienzo, {Celia J.} and Eggers, {Betsy J.} and Keith Riccardi and Shi, {Pei Yong} and Gong, {Yi Fei} and Browning, {Marc R.} and Qi Gao and Steven Hansel and Kenneth Santone and Lin, {Ping Fang} and Meanwell, {Nicholas A.} and Kadow, {John F.}",

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doi = "10.1016/j.bmcl.2012.10.115",

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AU - Qiu, Zhilei

AU - Xue, Quifen

AU - Fang, Haiquan

AU - Yang, Zheng

AU - Zadjura, Lisa

AU - D'Arienzo, Celia J.

AU - Eggers, Betsy J.

AU - Riccardi, Keith

AU - Shi, Pei Yong

AU - Gong, Yi Fei

AU - Browning, Marc R.

AU - Gao, Qi

AU - Hansel, Steven

AU - Santone, Kenneth

AU - Lin, Ping Fang

AU - Meanwell, Nicholas A.

AU - Kadow, John F.

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KW - Antivirals

KW - HIV-1 attachment inhibitors

KW - Indole glyoxamide

KW - Molecular conformation

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Inhibitors of HIV-1 attachment. Part 7: Indole-7-carboxamides as potent and orally bioavailable antiviral agents

Abstract

Keywords

ASJC Scopus subject areas

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