889804-90-4Relevant academic research and scientific papers
The discovery of a novel series of glucokinase activators based on a pyrazolopyrimidine scaffold
Bonn, Peter,Brink, D. Mikael,F?gerhag, Jonas,Jurva, Ulrik,Robb, Graeme R.,Schnecke, Volker,Svensson Henriksson, Anette,Waring, Michael J.,Westerlund, Christer
, p. 7302 - 7305 (2013/02/23)
Glucokinase is a key enzyme in glucose homeostasis since it phosphorylates glucose to give glucose-6-phosphate, which is the first step in glycolysis. GK activators have been proven to lower blood-glucose, and therefore have potential as treatments for type 2 diabetes. Here the discovery of pyrazolopyrimidine GKAs is reported. An original singleton hit from a high-throughput screen with micromolar levels of potency was optimised to give compounds with nanomolar activities. Key steps in this success were the introduction of an extra side-chain, which increased potency, and changing the linking functionality from a thioether to an ether, which led to improved potency and lipophilic ligand efficiency. This also led to more stable compounds with improved profiles in biological assays.
