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C5-Alkyl-2-methylurea-Substituted Pyridines as a New Class of Glucokinase Activators
Xiaohui Du1, Ronald J Hinklin2, Yumei Xiong1
1Amgen, Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
Abstract:
Glucokinase (GK) activators represent a class of type 2 diabetes therapeutics actively pursued due to the central role that GK plays in regulating glucose homeostasis. Herein we report a novel C5-alkyl-2-methylurea-substituted pyridine series of GK activators derived from our previously reported thiazolylamino pyridine series. Our efforts in optimizing potency, enzyme kinetic properties, and metabolic stability led to the identification of compound 26 (AM-9514). This analogue showed a favorable combination of in vitro potency, enzyme kinetic properties, acceptable pharmacokinetic profiles in preclinical species, and robust efficacy in a rodent PD model.
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