title: Discovery and hit-to-lead optimization of novel allosteric glucokinase activators.
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.
authors.affiliation: 4SC AG, Am Klopferspitz 19a, 82152 Planegg-Martinsried, Germany. mlang1.de@googlemail.com
authors.forename: Martin
authors.initials: M
authors.lastname: Lang
authors.forename: Markus H-J
authors.initials: MH
authors.lastname: Seifert
authors.forename: Kristina K
authors.initials: KK
authors.lastname: Wolf
authors.forename: Andrea
authors.initials: A
authors.lastname: Aschenbrenner
authors.forename: Roland
authors.initials: R
authors.lastname: Baumgartner
authors.forename: Tanja
authors.initials: T
authors.lastname: Wieber
authors.forename: Viola
authors.initials: V
authors.lastname: Trentinaglia
authors.forename: Marcus
authors.initials: M
authors.lastname: Blisse
authors.forename: Nobumitsu
authors.initials: N
authors.lastname: Tajima
authors.forename: Tokuyuki
authors.initials: T
authors.lastname: Yamashita
authors.forename: Daniel
authors.initials: D
authors.lastname: Vitt
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Noda
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D020536:Enzyme Activators / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005941:Glucokinase / Q000378:metabolism*; D006860:Hydrogen Bonding; D008958:Models, Molecular; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D020536:Enzyme Activators; D005941:Glucokinase