- Discovery of an intravenous hepatoselective glucokinase activator for the treatment of inpatient hyperglycemia
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Glucokinase (hexokinase IV) continues to be a compelling target for the treatment of type 2 diabetes given the wealth of supporting human genetics data and numerous reports of robust clinical glucose lowering in patients treated with small molecule allosteric activators. Recent work has demonstrated the ability of hepatoselective activators to deliver glucose lowering efficacy with minimal risk of hypoglycemia. While orally administered agents require a considerable degree of passive permeability to promote suitable exposures, there is no such restriction on intravenously delivered drugs. Therefore, minimization of membrane diffusion in the context of an intravenously agent should ensure optimal hepatic targeting and therapeutic index. This work details the identification a hepatoselective GKA exhibiting the aforementioned properties.
- Stevens, Benjamin D.,Litchfield, John,Pfefferkorn, Jeffrey A.,Atkinson, Karen,Perreault, Christian,Amor, Paul,Bahnck, Kevin,Berliner, Martin A.,Calloway, Jessica,Carlo, Anthony,Derksen, David R.,Filipski, Kevin J.,Gumkowski, Mike,Jassal, Charanjeet,MacDougall, Margit,Murphy, Brendan,Nkansah, Paul,Pettersen, John,Rotter, Charles,Zhang, Yan
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- HETEROARYLS AMIDE DERIVATIVES AND THEIR USE AS GLUCOKINASE ACTIVATORS
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The present invention provides Formula (1A) compounds that act as glucokinase activators; pharmaceutical compositions thereof; and methods of treating diseases, disorders, or conditions mediated by glucokinase. X, Y, Z, R1, R2, R3, and R4 are as described herein.
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(2010/04/06)
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