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Discovery of a Partial Glucokinase Activator Clinical Candidate: Diethyl ((3-(3-((5-(Azetidine-1-carbonyl)pyrazin-2-yl)oxy)-5-isopropoxybenzamido)-1-pyrazol-1-yl)methyl)phosphonate (BMS-820132). | LitMetric
Glucokinase (GK) is a key regulator of glucose homeostasis, and its small-molecule activators represent a promising opportunity for the treatment of type 2 diabetes. Several GK activators have been advanced into clinical trials and have demonstrated promising efficacy; however, hypoglycemia represents a key risk for this mechanism. In an effort to mitigate this hypoglycemia risk while maintaining the efficacy of the GK mechanism, we have investigated a series of amino heteroaryl phosphonate benzamides as ''partial" GK activators. The structure-activity relationship studies starting from a "full GK activator" , which culminated in the discovery of the "partial GK activator" (BMS-820132), are discussed. The synthesis and and preclinical pharmacology profiles of and its pharmacokinetics (PK) are described. Based on its promising efficacy and preclinical ADME and safety profiles, was advanced into human clinical trials.
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diethyl 3-3-5-azetidine-1-carbonylpyrazin-2-yloxy-5-isopropoxybenzamido-1-pyrazol-1-ylmethylphosphonate
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3-3-5-azetidine-1-carbonylpyrazin-2-yloxy-5-isopropoxybenzamido-1-pyrazol-1-ylmethylphosphonate bms-820132
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