ABSTRACT
A directed screen of a relatively small number of compounds, selected for kinase ATP pocket binding potential, yielded a novel series of hit compounds (1). Hit explosion on two binding residues identified compounds 27 and 43 as the best leads for an optimization program having reduced secondary metabolism, as measured by in vitro rat hepatocytes incubation, leading to oral bio-availability. Structure-activity relationships and molecular modeling have suggested a binding mode for the most potent inhibitor 12.
Subject(s)
Anilides/pharmacology , Drug Discovery , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Anilides/chemical synthesis , Anilides/chemistry , Crystallography, X-Ray , Dose-Response Relationship, Drug , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins c-met/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The continued optimization of a series of glucokinase activators is described, including attempts to understand the interplay between molecular structure and the composite parameter of unbound clearance. These studies resulted in the discovery of a new scaffold for glucokinase activators and further exploration of this scaffold led to the identification of GKA60. GKA60 maintains an excellent balance of potency and physical properties whilst possessing a significantly different, but complimentary, pre-clinical pharmacokinetic profile compared with the previously disclosed compound GKA50.
Subject(s)
Drug Design , Enzyme Activation/drug effects , Enzyme Activators/chemical synthesis , Enzyme Activators/pharmacology , Glucokinase/metabolism , Hypoglycemic Agents/chemistry , Animals , Dogs , Half-Life , Humans , Hypoglycemic Agents/pharmacology , Molecular Structure , Pyridines/pharmacology , Rats , Solubility , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Enzyme Activators/chemistry , Enzyme Activators/pharmacology , Glucokinase/metabolism , Drug Design , Enzyme Activators/pharmacokineticsABSTRACT
The identification, synthesis and SAR of a novel series of glucokinase activators is described. The interplay between lipophilicity, potency and physical properties is discussed, and compound 22 highlighted as having a suitable balance. In vivo pharmacokinetic and acute efficacy studies on this compound are also presented.
