2. Academic Validation
  3. Discovery and hit-to-lead optimization of novel allosteric glucokinase activators

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

  • Bioorg Med Chem Lett. 2011 Sep 15;21(18):5417-22. doi: 10.1016/j.bmcl.2011.06.128.
Martin Lang 1,  Markus H-J Seifert,  Kristina K Wolf,  Andrea Aschenbrenner,  Roland Baumgartner,  Tanja Wieber,  Viola Trentinaglia,  Marcus Blisse,  Nobumitsu Tajima,  Tokuyuki Yamashita,  Daniel Vitt,  Hitoshi Noda
Affiliations

Affiliation

  • 1 4SC AG, Am Klopferspitz 19a, 82152 Planegg-Martinsried, Germany. mlang1.de@googlemail.com
PMID: 21813277 DOI: 10.1016/j.bmcl.2011.06.128
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 motif followed by further studies eventually furnished a series of potent lead compounds exhibiting steep SAR.

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