Sulfonamides as Selective Na V 1.7 Inhibitors: Optimizing Potency and Pharmacokinetics to Enable in Vivo Target Engagement

Human genetic evidence has identified the voltage-gated sodium channel Na 1.7 as an attractive target for the treatment of pain. We initially identified naphthalene sulfonamide as a potent and selective inhibitor of Na 1.7. Optimization to reduce biliary clearance by balancing hydrophilicity and hyd...

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Published inACS medicinal chemistry letters Vol. 7; no. 12; pp. 1062 - 1067
Main Authors Marx, Isaac E, Dineen, Thomas A, Able, Jessica, Bode, Christiane, Bregman, Howard, Chu-Moyer, Margaret, DiMauro, Erin F, Du, Bingfan, Foti, Robert S, Fremeau, Jr, Robert T, Gao, Hua, Gunaydin, Hakan, Hall, Brian E, Huang, Liyue, Kornecook, Thomas, Kreiman, Charles R, La, Daniel S, Ligutti, Joseph, Lin, Min-Hwa Jasmine, Liu, Dong, McDermott, Jeff S, Moyer, Bryan D, Peterson, Emily A, Roberts, Jonathan T, Rose, Paul, Wang, Jean, Youngblood, Beth D, Yu, Violeta, Weiss, Matthew M
Format Journal Article
LanguageEnglish
Published United States 08.12.2016
Subjects
histamine scratching model
pain
Sodium channel
NaV1.5
NaV1.7
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Summary:Human genetic evidence has identified the voltage-gated sodium channel Na 1.7 as an attractive target for the treatment of pain. We initially identified naphthalene sulfonamide as a potent and selective inhibitor of Na 1.7. Optimization to reduce biliary clearance by balancing hydrophilicity and hydrophobicity (Log ) while maintaining Na 1.7 potency led to the identification of quinazoline (AM-2099). Compound 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.
ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.6b00243