The discovery of a novel series of glucokinase activators based on a pyrazolopyrimidine scaffold
| Autor: | Jonas Fägerhag, Christer Westerlund, Graeme R. Robb, Ulrik Jurva, Henriksson Anette Marie Svensson, Peter Bonn, Volker Schnecke, D. Mikael Brink, Michael J. Waring |
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| Rok vydání: | 2012 |
| Předmět: |
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Molecular Clinical Biochemistry Pharmaceutical Science Biochemistry Pyrazolopyrimidine Structure-Activity Relationship chemistry.chemical_compound Enzyme activator Thioether Glucokinase Drug Discovery Glucose homeostasis Potency Glycolysis Molecular Biology Ligand efficiency Dose-Response Relationship Drug Molecular Structure Organic Chemistry High-Throughput Screening Assays Enzyme Activation Pyrimidines chemistry Pyrazoles Molecular Medicine |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 22:7302-7305 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2012.10.090 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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