The discovery and optimization of benzimidazoles as selective NaV1.8 blockers for the treatment of pain

被引：15

作者：

Brown, Alan D. ^{[1
]}

Bagal, Sharan K. ^{[1
]}

Blackwell, Paul ^{[2
]}

Blakemore, David C. ^{[4
]}

Brown, Bruce ^{[2
]}

Bungay, Peter J. ^{[3
]}

Corless, Martin ^{[2
]}

Crawforth, James ^{[2
]}

Fengas, David ^{[5
]}

Fenwick, David R. ^{[2
]}

Gray, Victoria ^{[2
]}

Kemp, Mark ^{[2
]}

Klute, Wolfgang ^{[2
]}

Sanz, Laia Malet ^{[2
]}

Miller, Duncan ^{[2
]}

Murata, Yoshihisa ^{[2
]}

Payne, C. Elizabeth ^{[3
]}

Skerratt, Sarah ^{[1
]}

Stevens, Edward B. ^{[3
]}

Warmus, Joseph S. ^{[4
]}

机构：

[1] Pfizer Ltd, Pfizer Med Design, Portway Bldg,Granta Pk, Cambridge CB21 6GS, England

[2] Pfizer Global R&D, Pfizer Med Sci, Sandwich CT13 9FF, Kent, England

[3] Pfizer Ltd, Med Sci, Portway Bldg,Granta Pk, Cambridge CB21 6GS, England

[4] Groton Labs, Pfizer Med Design, Eastern Point Rd, Groton, CT 06340 USA

[5] Concept Life Sci, Discovery Pk,Ramsgate Rd, Sandwich CT13 9FF, Kent, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2019年 / 27卷 / 01期

关键词：

Benzimidazole; PF-06305591; Neuropathic pain; Inflammatory pain; Voltage gated sodium channel; Na(V)1.8; SCN10A; INHIBITORS; MUTATIONS; POTENT;

D O I：

10.1016/j.bmc.2018.12.002

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：

The voltage gated sodium channel Na(V)1.8 has been postulated to play a key role in the transmission of pain signals. Core hopping from our previously reported phenylimidazole leads has allowed the identification of a novel series of benzimidazole Na(V)1.8 blockers. Subsequent optimization allowed the identification of compound 9, PF-06305591, as a potent, highly selective blocker with an excellent preclinical in vitro ADME and safety profile.

引用

页码：230 / 239

页数：10

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