Discovery and hit-to-lead optimization of novel allosteric glucokinase activators

We report on a hit generation and hit-to-lead program of a novel class of glucokinase activators (GKAs). Hit compounds, activators at low glucose concentration only were identified by vHTS. Scaffold modification reliably afforded activators also at high substrate level. Potency was increased by intr...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2011-09, Vol.21 (18), p.5417-5422
Main Authors: Lang, Martin, Seifert, Markus H.-J., Wolf, Kristina K., Aschenbrenner, Andrea, Baumgartner, Roland, Wieber, Tanja, Trentinaglia, Viola, Blisse, Marcus, Tajima, Nobumitsu, Yamashita, Tokuyuki, Vitt, Daniel, Noda, Hitoshi
Format: Article
Language:English
Subjects:
Allosteric activators
Allosteric Regulation - drug effects
Biological and medical sciences
Dose-Response Relationship, Drug
Drug Discovery
Enzyme Activators - chemical synthesis
Enzyme Activators - chemistry
Enzyme Activators - pharmacology
General and cellular metabolism. Vitamins
Glucokinase
Glucokinase - metabolism
glucose
Hit-to-lead optimization
Hydrogen Bonding
Medical sciences
Models, Molecular
Molecular modeling
Molecular Structure
Pharmacology. Drug treatments
Stereoisomerism
Structure-Activity Relationship
Type 2 diabetes
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Summary:We report on a hit generation and hit-to-lead program of a novel class of glucokinase activators (GKAs). Hit compounds, activators at low glucose concentration only were identified by vHTS. Scaffold modification reliably afforded activators also at high substrate level. Potency was increased by introduction of a hydrogen bond acceptor as proposed by molecular docking. Replacement of the initial alkylene linkers with a rigid 1,2-phenylene motif followed by further studies eventually furnished a series of potent lead compounds exhibiting steep SAR.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2011.06.128