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

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

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. ",

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

language = "English (US)",

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journal = "Bioorganic and Medicinal Chemistry Letters",

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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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JF - Bioorganic and Medicinal Chemistry Letters

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ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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