The discovery of a potent series of carboxamide TRPA1 antagonists

被引：7

作者：

Pryde, D. C. ^{[1
,6
]}

Marron, B. ^{[2
]}

West, C. G. ^{[2
]}

Reister, S. ^{[2
]}

Amato, G. ^{[2
]}

Yoger, K. ^{[2
]}

Padilla, K. ^{[2
]}

Turner, J. ^{[3
]}

Swain, N. A. ^{[1
]}

Cox, P. J. ^{[3
]}

Skerratt, S. E. ^{[1
]}

Ryckmans, T. ^{[4
]}

Blakemore, D. C. ^{[1
]}

Warmus, J. ^{[5
]}

Gerlach, A. C. ^{[2
]}

机构：

[1] Pfizer Worldwide Med Chem, Neurosci & Pain Res Unit, Portway Bldg,Granta Pk, Great Abington CB21 6GS, Cambs, England

[2] Icagen Inc, 4222 Emperor Blvd,Suite 350, Durham, NC 27703 USA

[3] Neurosci & Pain Res Unit, Portway Bldg,Granta Pk, Great Abington CB21 6GS, Cambs, England

[4] Pfizer Worldwide Med Chem, Ramsgate Rd, Sandwich CT13 9NJ, Kent, England

[5] Pfizer Worldwide Med Chem, Neurosci & Pain Res Unit, Groton, CT USA

[6] Curadev UK, Innovat House,Discovery Pk, Sandwich CT14 9FF, Kent, England

来源：

MEDCHEMCOMM | 2016年 / 7卷 / 11期

关键词：

BIOLOGICAL EVALUATION; CHANNEL TRPA1; DRUG TARGETS; RECEPTOR; PAIN; INFLAMMATION; ACTIVATE; NEURONS; TRPV1; COLD;

D O I：

10.1039/c6md00387g

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A series of potent and selective carboxamide TRPA1 antagonists were identified by a high throughput screen. Structure-activity relationship studies around this series are described, resulting in a highly potent example of the series. Pharmacokinetic and skin flux data are presented for this compound. Efficacy was observed in a topical cinnamaldehyde flare study, providing a topical proof of pharmacology for this mechanism. These data suggest TRPA1 antagonism could be a viable mechanism to treat topical conditions such as atopic dermatitis.

引用

页码：2145 / 2158

页数：14

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