1361215-55-5Relevant academic research and scientific papers
Small molecule disruptors of the Glucokinase-Glucokinase regulatory protein interaction: 1. Discovery of a novel tool compound for in vivo proof-of-concept
Ashton, Kate S.,Andrews, Kristin L.,Bryan, Marion C.,Chen, Jie,Chen, Kui,Chen, Michelle,Chmait, Samer,Croghan, Michael,Cupples, Rod,Fotsch, Christopher,Helmering, Joan,Jordan, Steve R.,Kurzeja, Robert J. M.,Michelsen, Klaus,Pennington, Lewis D.,Poon, Steve F.,Sivits, Glenn,Van, Gwyneth,Vonderfecht, Steve L.,Wahl, Robert C.,Zhang, Jiandong,Lloyd, David J.,Hale, Clarence,St. Jean, David J.
, p. 309 - 324 (2014/02/14)
Small molecule activators of glucokinase have shown robust efficacy in both preclinical models and humans. However, overactivation of glucokinase (GK) can cause excessive glucose turnover, leading to hypoglycemia. To circumvent this adverse side effect, we chose to modulate GK activity by targeting the endogenous inhibitor of GK, glucokinase regulatory protein (GKRP). Disrupting the GK-GKRP complex results in an increase in the amount of unbound cytosolic GK without altering the inherent kinetics of the enzyme. Herein we report the identification of compounds that efficiently disrupt the GK-GKRP interaction via a previously unknown binding pocket. Using a structure-based approach, the potency of the initial hit was improved to provide 25 (AMG-1694). When dosed in ZDF rats, 25 showed both a robust pharmacodynamic effect as well as a statistically significant reduction in glucose. Additionally, hypoglycemia was not observed in either the hyperglycemic or normal rats.
A general method for the facile synthesis of optically active 2-substituted piperazines via functionalized 2,5-diketopiperazines
Ashton, Kate S.,Denti, Mitchell,Norman, Mark H.,St. Jean Jr., David J.
, p. 4501 - 4504 (2014/08/05)
Upon utilization of some common methods described in the literature for the synthesis of chiral, 2-substituted 2,5-diketopiperazines, extensive racemization was observed. Further investigation showed that heating in the presence of a mild base racemized the chiral center in the product diketopiperazines. A generalized, readily scalable route was sought and, after investigating the effect of base and temperature, conditions were identified that promoted cyclization without erosion of enantiomeric excess. An array of functionalization was tolerated and this procedure serves as a useful and reliable method for the facile synthesis of this important class of compounds.
