Structure-activity relationships of trimethoxybenzyl piperazine N-type calcium channel inhibitors

Hassan Pajouhesh; Zhong Ping Feng; Lingyun Zhang; Hossein Pajouhesh; Xinpo Jiang; Adam Hendricson; Haiheng Dong; Elizabeth Tringham; Yanbing Ding; Todd W. Vanderah; Frank Porreca; Francesco Belardetti; Gerald W. Zamponi; Lester A. Mitscher; Terrance P. Snutch

doi:10.1016/j.bmcl.2012.04.054

Structure-activity relationships of trimethoxybenzyl piperazine N-type calcium channel inhibitors

Hassan Pajouhesh, Zhong Ping Feng, Lingyun Zhang, Hossein Pajouhesh, Xinpo Jiang, Adam Hendricson, Haiheng Dong, Elizabeth Tringham, Yanbing Ding, Todd W. Vanderah, Frank Porreca, Francesco Belardetti, Gerald W. Zamponi, Lester A. Mitscher, Terrance P. Snutch

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26 Scopus citations

Abstract

We previously reported the small organic N-type calcium channel blocker NP078585 that while efficacious in animal models for pain, exhibited modest L-type calcium channel selectivity and substantial off-target inhibition against the hERG potassium channel. Structure-activity studies to optimize NP078585 preclinical properties resulted in compound 16, which maintained high potency for N-type calcium channel blockade, and possessed excellent selectivity over the hERG (∼120-fold) and L-type (∼3600-fold) channels. Compound 16 shows significant anti-hyperalgesic activity in the spinal nerve ligation model of neuropathic pain and is also efficacious in the rat formalin model of inflammatory pain.

Original language	English (US)
Pages (from-to)	4153-4158
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	22
Issue number	12
DOIs	https://doi.org/10.1016/j.bmcl.2012.04.054
State	Published - Jun 15 2012

Keywords

L-Type calcium channel
N-Type calcium channel
Pain
Trimethoxybenzyl piperazine
hERG potassium channel

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.2012.04.054

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Pajouhesh, H., Feng, Z. P., Zhang, L., Pajouhesh, H., Jiang, X., Hendricson, A., Dong, H., Tringham, E., Ding, Y., Vanderah, T. W., Porreca, F., Belardetti, F., Zamponi, G. W., Mitscher, L. A., & Snutch, T. P. (2012). Structure-activity relationships of trimethoxybenzyl piperazine N-type calcium channel inhibitors. Bioorganic and Medicinal Chemistry Letters, 22(12), 4153-4158. https://doi.org/10.1016/j.bmcl.2012.04.054

Pajouhesh, H, Feng, ZP, Zhang, L, Pajouhesh, H, Jiang, X, Hendricson, A, Dong, H, Tringham, E, Ding, Y, Vanderah, TW , Porreca, F, Belardetti, F, Zamponi, GW, Mitscher, LA & Snutch, TP 2012, 'Structure-activity relationships of trimethoxybenzyl piperazine N-type calcium channel inhibitors', Bioorganic and Medicinal Chemistry Letters, vol. 22, no. 12, pp. 4153-4158. https://doi.org/10.1016/j.bmcl.2012.04.054

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title = "Structure-activity relationships of trimethoxybenzyl piperazine N-type calcium channel inhibitors",

abstract = "We previously reported the small organic N-type calcium channel blocker NP078585 that while efficacious in animal models for pain, exhibited modest L-type calcium channel selectivity and substantial off-target inhibition against the hERG potassium channel. Structure-activity studies to optimize NP078585 preclinical properties resulted in compound 16, which maintained high potency for N-type calcium channel blockade, and possessed excellent selectivity over the hERG (∼120-fold) and L-type (∼3600-fold) channels. Compound 16 shows significant anti-hyperalgesic activity in the spinal nerve ligation model of neuropathic pain and is also efficacious in the rat formalin model of inflammatory pain.",

keywords = "L-Type calcium channel, N-Type calcium channel, Pain, Trimethoxybenzyl piperazine, hERG potassium channel",

author = "Hassan Pajouhesh and Feng, {Zhong Ping} and Lingyun Zhang and Hossein Pajouhesh and Xinpo Jiang and Adam Hendricson and Haiheng Dong and Elizabeth Tringham and Yanbing Ding and Vanderah, {Todd W.} and Frank Porreca and Francesco Belardetti and Zamponi, {Gerald W.} and Mitscher, {Lester A.} and Snutch, {Terrance P.}",

note = "Funding Information: Work in the laboratories of T.P.S. and G.W.Z. is supported by the Canadian Institutes of Health Research. T.P.S. is a Canada Research Chair in Biotechnology and Genomics-Neurobiology. G.W.Z. is a Scientist of the Alberta Heritage Foundation for Medical Research and is also supported by a Canada Research Chair in Molecular Neurobiology. ",

year = "2012",

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doi = "10.1016/j.bmcl.2012.04.054",

language = "English (US)",

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AU - Pajouhesh, Hassan

AU - Feng, Zhong Ping

AU - Zhang, Lingyun

AU - Pajouhesh, Hossein

AU - Jiang, Xinpo

AU - Hendricson, Adam

AU - Dong, Haiheng

AU - Tringham, Elizabeth

AU - Ding, Yanbing

AU - Vanderah, Todd W.

AU - Porreca, Frank

AU - Belardetti, Francesco

AU - Zamponi, Gerald W.

AU - Mitscher, Lester A.

AU - Snutch, Terrance P.

N1 - Funding Information: Work in the laboratories of T.P.S. and G.W.Z. is supported by the Canadian Institutes of Health Research. T.P.S. is a Canada Research Chair in Biotechnology and Genomics-Neurobiology. G.W.Z. is a Scientist of the Alberta Heritage Foundation for Medical Research and is also supported by a Canada Research Chair in Molecular Neurobiology.

PY - 2012/6/15

Y1 - 2012/6/15

N2 - We previously reported the small organic N-type calcium channel blocker NP078585 that while efficacious in animal models for pain, exhibited modest L-type calcium channel selectivity and substantial off-target inhibition against the hERG potassium channel. Structure-activity studies to optimize NP078585 preclinical properties resulted in compound 16, which maintained high potency for N-type calcium channel blockade, and possessed excellent selectivity over the hERG (∼120-fold) and L-type (∼3600-fold) channels. Compound 16 shows significant anti-hyperalgesic activity in the spinal nerve ligation model of neuropathic pain and is also efficacious in the rat formalin model of inflammatory pain.

AB - We previously reported the small organic N-type calcium channel blocker NP078585 that while efficacious in animal models for pain, exhibited modest L-type calcium channel selectivity and substantial off-target inhibition against the hERG potassium channel. Structure-activity studies to optimize NP078585 preclinical properties resulted in compound 16, which maintained high potency for N-type calcium channel blockade, and possessed excellent selectivity over the hERG (∼120-fold) and L-type (∼3600-fold) channels. Compound 16 shows significant anti-hyperalgesic activity in the spinal nerve ligation model of neuropathic pain and is also efficacious in the rat formalin model of inflammatory pain.

KW - L-Type calcium channel

KW - N-Type calcium channel

KW - Pain

KW - Trimethoxybenzyl piperazine

KW - hERG potassium channel

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Structure-activity relationships of trimethoxybenzyl piperazine N-type calcium channel inhibitors

Abstract

Keywords

ASJC Scopus subject areas

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