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

…, A Aschenbrenner, R Baumgartner, T Wieber…

Index: 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 Bioorganic and Medicinal Chemistry Letters, 2011 , vol. 21, # 18 p. 5417 - 5422

Full Text: HTML

Citation Number: 13

Abstract

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 ...