1. The discovery of a novel series of glucokinase activators based on a pyrazolopyrimidine scaffold
- Author
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Bonn, Peter, Brink, D. Mikael, Fägerhag, Jonas, Jurva, Ulrik, Robb, Graeme R., Schnecke, Volker, Svensson Henriksson, Anette, Waring, Michael J., and Westerlund, Christer
- Subjects
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GLUCOKINASE , *PYRIMIDINES , *ENZYME kinetics , *HOMEOSTASIS , *GLUCOSE-6-phosphatase , *GLYCOLYSIS , *LIGANDS (Biochemistry) - Abstract
Abstract: 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. [Copyright &y& Elsevier]
- Published
- 2012
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