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

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.

[1]  J. Grippo,et al.  Allosteric Activators of Glucokinase: Potential Role in Diabetes Therapy , 2003, Science.

[2]  M. Nawano,et al.  Glucokinase-activating ureas. , 2005, Bioorganic & medicinal chemistry letters.

[3]  M. Tadayyon,et al.  Insulin sensitisation in the treatment of Type 2 diabetes , 2003, Expert opinion on investigational drugs.

[4]  F. Matschinsky.  Regulation of Pancreatic β-Cell Glucokinase: From Basics to Therapeutics , 2002 .

[5]  G. Robbie,et al.  Correlation of Plasma Clearance of 54 Extensively Metabolized Drugs Between Humans and Rats: Mean Allometric Coefficient of 0.66 , 1998, Pharmaceutical Research.

[6]  H. Najafi,et al.  Glucokinase and glucose homeostasis: proven concepts and new ideas. , 2005, Biochemical Society transactions.

[7]  J. Gromada,et al.  A novel glucokinase activator modulates pancreatic islet and hepatocyte function. , 2005, Endocrinology.

[8]  M. Coghlan,et al.  Stimulation of hepatocyte glucose metabolism by novel small molecule glucokinase activators. , 2004, Diabetes.

[9]  Scott Boyd,et al.  Discovery, synthesis and biological evaluation of novel glucokinase activators. , 2005, Bioorganic & medicinal chemistry letters.

[10]  E. Kilgour,et al.  PDH kinase inhibitors: a novel therapy for Type II diabetes? , 2005, Biochemical Society transactions.

[11]  Teruyuki Nishimura,et al.  Structural basis for allosteric regulation of the monomeric allosteric enzyme human glucokinase. , 2004, Structure.

[12]  Leland J. Gershell.  Type 2 diabetes market , 2005, Nature Reviews Drug Discovery.

[13]  M. Coghlan,et al.  Small molecule glucokinase activators as novel anti-diabetic agents. , 2005, Biochemical Society transactions.

[14]  M. Delp,et al.  Physiological Parameter Values for Physiologically Based Pharmacokinetic Models , 1997, Toxicology and industrial health.

[15]  Giuseppe d'Annunzio,et al.  Insights into the Structure and Regulation of Glucokinase from a Novel Mutation (V62M), Which Causes Maturity-onset Diabetes of the Young* , 2005, Journal of Biological Chemistry.