Design of a potent, soluble glucokinase activator with excellent in vivo efficacy

Bioorganic & Medicinal Chemistry Letters
D McKerrecherRolf P Walker

Abstract

The optimisation of a series of glucokinase activators is described, including attempts to uncouple the relationship between potency and plasma protein binding, and to better understand the key pharmacokinetic properties of the series. The use of unbound clearance as an optimisation parameter facilitated the identification of GKA50, a compound which combines excellent potency and pharmacokinetics with good free drug levels and solubility, and exhibits in vivo efficacy at 1mg/kg po in an acute rat OGTT model.

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Citations

Jul 9, 2013·Bioorganic & Medicinal Chemistry Letters·Kevin J FilipskiJeffrey A Pfefferkorn
Jul 3, 2013·European Journal of Pharmacology·Didier LaurentAlokesh Duttaroy
Dec 2, 2010·Nature Reviews. Drug Discovery·Dennis A SmithEdward H Kerns
Jan 1, 2007·Expert Opinion on Drug Discovery·George L Trainor
Jan 31, 2008·Expert Opinion on Investigational Drugs·Matthew Coghlan, Brendan Leighton
Jun 27, 2013·Journal of Pharmaceutical Sciences·Tonika Bohnert, Liang-Shang Gan
Oct 16, 2008·Medicinal Research Reviews·Michael L MohlerDuane D Miller
Feb 17, 2015·Analytical Biochemistry·O AssematM-A Delsuc
Jan 13, 2015·Journal of Molecular Graphics & Modelling·Mutasem O TahaAmjad Qandil
Nov 7, 2007·Thérapie·Murielle Combettes, Catherine Kargar
Apr 10, 2017·European Journal of Medicinal Chemistry·Anil M DeshpandeKasim A Mookhtiar
Mar 23, 2017·Computational Biology and Chemistry·Nanda Kumar YellapuBhaskar Matcha
Mar 13, 2012·Pharmacological Reviews·E J Verspohl
Oct 25, 2007·Biochemical Society Transactions·D JohnsonM J Dunne
Apr 11, 2014·Journal of Biomolecular Screening·Kui ChenRobert C Wahl
Mar 29, 2008·Biochemistry·Erik C RalphShaoxian Sun
Oct 4, 2018·Journal of Medicinal Chemistry·Dennis A SmithLi Di
Apr 11, 2013·ACS Medicinal Chemistry Letters·Yimin QianNavita L Mallalieu

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