Glucokinase (GK) is an enzyme in the hexokinase family that plays a pivotal role in blood glucose homeostasis. Allosteric activation of GK with small molecules has been shown to lower blood glucose levels in rodents as well as in human clinical trials. Although this class of therapeutics have demonstrated robust efficacy, a potentially serious side effect is hypoglycemia as a result of over activation of GK. To address this liability, our team has initiated a program designed to target GK pathway by inhibiting the interaction of GK with its liver-specific glucokinase regulatory protein (GKRP). In this poster we report the results of our expanded SAR investigation of the N-arylsulfonyl-N-2-pyridinyl-piperazine series that focused on the 6-position of the N-pyridine ring. These studies resulted in the discovery of 2-(2-(4-((6-aminopyridin-3-yl)sulfonyl)piperazin-1-yl)-[3,3'-bipyridin]-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol. The X-ray co-crystal data showed that the 3-pyridine ring of this compound bound in a novel area of the GKRP protein. This compound was potent in the biochemical and cellular assays for GK-GKRP and exhibited favorable PK properties for in vivo evaluation. When administered orally to db/db mice this compound demonstrated a robust pharmacodynamic response, and led to a significant reduction in plasma glucose levels.

Optimization of a series of an N-arylsulfonamido-N'-aryl-piperazine GK-GKRP modulators: Exploration of a novel binding pocket in GKRP

247th National Meeting (2014)

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