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The discovery of a novel series of glucokinase activators based on a pyrazolopyrimidine scaffold.

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.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Bonn P,Brink DM,Fägerhag J,Jurva U,Robb GR,Schnecke V,Svensson Henriksson A,Waring MJ,Westerlund C

doi

10.1016/j.bmcl.2012.10.090

subject

Has Abstract

pub_date

2012-12-15 00:00:00

pages

7302-5

issue

24

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(12)01381-9

journal_volume

22

pub_type

杂志文章

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