期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 7, 期 12, 页码 1062-1067出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.6b00243
关键词
Sodium channel; Na(v)1.7; Na(v)1.5; pain; histamine scratching model
Human genetic evidence has identified the voltage-gated sodium channel Na(v)1.7 as an attractive target for the treatment of pain. We initially identified naphthalene sulfonamide 3 as a potent and selective inhibitor of Na(v)1.7. Optimization to reduce biliary clearance by balancing hydrophilicity and hydrophobicity (Log D) while maintaining Na(v)1.7 potency led to the identification of quinazoline 16 (AM-2099). Compound 16 demonstrated a favorable pharmacokinetic profile in rat and dog and demonstrated dose-dependent reduction of histamine-induced scratching bouts in a mouse behavioral model following oral dosing.
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