The discovery of a novel series of glucokinase activators based on a pyrazolopyrimidine scaffold.

Glucokinase is a key enzyme in glucose homeostasis since it phosphorylates glucose to give glucose-6-phosphate, which is the first step in glycolysis. GK activators have been proven to lower blood-glucose, and therefore have potential as treatments for type 2 diabetes. Here the discovery of pyrazolopyrimidine GKAs is reported. An original singleton hit from a high-throughput screen with micromolar levels of potency was optimised to give compounds with nanomolar activities. Key steps in this success were the introduction of an extra side-chain, which increased potency, and changing the linking functionality from a thioether to an ether, which led to improved potency and lipophilic ligand efficiency. This also led to more stable compounds with improved profiles in biological assays.

[1]  Michael J. Waring,et al.  Matrix-based multiparameter optimisation of glucokinase activators: the discovery of AZD1092 , 2011 .

[2]  Michael J. Waring,et al.  Property based optimisation of glucokinase activators – discovery of the phase IIb clinical candidate AZD1656 , 2012 .

[3]  Roland K. Robins,et al.  Potential Purine Antagonists. VI. Synthesis of 1-Alkyl- and 1-Aryl-4-substituted Pyrazolo[3,4-d]pyrimidines , 1956 .

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

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

[6]  P. Siekevitz,et al.  ENZYME-STRUCTURE RELATIONSHIPS IN THE ENDOPLASMIC RETICULUM OF RAT LIVER , 1962, The Journal of cell biology.

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

[8]  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.

[9]  A. Hopkins,et al.  Ligand efficiency: a useful metric for lead selection. , 2004, Drug discovery today.

[10]  M. Coghlan,et al.  Glucokinase activators in diabetes management , 2008, Expert opinion on investigational drugs.

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

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

[13]  F. Matschinsky,et al.  Assessing the potential of glucokinase activators in diabetes therapy , 2009, Nature Reviews Drug Discovery.

[14]  Craig S Donald,et al.  Design of a potent, soluble glucokinase activator with excellent in vivo efficacy. , 2006, Bioorganic & medicinal chemistry letters.

[15]  H. Lazrek,et al.  Synthesis of Some 4‐Substituted 1‐(4‐Hydroxybutyl)Pyrazolo‐[3,4‐D]Pyrimidine Analogues of 9‐(4‐Hydroxybutyl)Guanine (HBG) , 2010 .

[16]  M. Fyfe,et al.  Glucokinase activators as potential antidiabetic agents possessing superior glucose lowering efficacies , 2009, Drugs of the Future.

[17]  D. Mckerrecher,et al.  Design of a potent, soluble glucokinase activator with increased pharmacokinetic half-life. , 2011, Bioorganic & medicinal chemistry letters.

[18]  Michael J. Waring,et al.  Overcoming retinoic acid receptor-α based testicular toxicity in the optimisation of glucokinase activators , 2011 .

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

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