Discovery of a Novel Class of State-Dependent NaV1.7 Inhibitors for the Treatment of Neuropathic Pain

Autor:	Yutaka Kitano, Chie Fujiwara, Sayaka Suzuki, Ryuta Koishi, Tomihisa Yokoyama, Satoshi Shibuya, Daigo Asano, Yuki Domon, Kyosuke Tanaka, Hiroko Kimoto, Akiko Shimizugawa, Tsuyoshi Shinozuka, Kazufumi Kubota, Hiroyuki Kobayashi
Rok vydání:	2020
Předmět:	biology Chemistry medicine.drug_class Sodium channel hERG Analgesic Central nervous system General Chemistry General Medicine Pharmacology Quinolone medicine.anatomical_structure Drug Discovery Neuropathic pain NAV1 biology.protein medicine ED50
Zdroj:	Chemical and Pharmaceutical Bulletin. 68:653-663
ISSN:	1347-5223 0009-2363
Popis:	The discovery of a novel class of state-dependent voltage-gated sodium channel (NaV)1.7 inhibitors is described. By the modification of amide or urethane bond in NaV1.7 blocker III, structure-activity relationship studies that led to the identification of novel NaV1.7 inhibitor 2i (DS01171986) were performed. Compound 2i exhibited state-dependent inhibition of NaV1.7 without NaV1.1, NaV1.5 or human ether-a-go-go related gene (hERG) liabilities at concentrations up to 100 μM. Further biological profiling successfully revealed that 2i possessed potent analgesic properties in a murine model of neuropathic pain (ED50: 3.4 mg/kg) with an excellent central nervous system (CNS) safety margin (> 600 fold).
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_________::89845e45af2cb38ea79da89f3f6a10c8 https://doi.org/10.1248/cpb.c20-00126 Zobrazit plný text záznamu