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Bioorg Med Chem Lett. 2013 Dec 15;23(24):6588-92. doi: 10.1016/j.bmcl.2013.10.057. Epub 2013 Nov 4.

Discovery of an intravenous hepatoselective glucokinase activator for the treatment of inpatient hyperglycemia.

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Cambridge Laboratories, Pfizer Worldwide Research & Development, 620 Memorial Drive, Cambridge, MA 02139, United States. Electronic address:


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.


Allosteric; Diabetes; Glucokinase; Hepatoselective; OATP

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