ABSTRACT
An 1,3-oxybenzylglycine based compound 2 (BMS-687453) was discovered to be a potent and selective peroxisome proliferator activated receptor (PPAR) alpha agonist, with an EC(50) of 10 nM for human PPARalpha and approximately 410-fold selectivity vs human PPARgamma in PPAR-GAL4 transactivation assays. Similar potencies and selectivity were also observed in the full length receptor co-transfection assays. Compound 2 has negligible cross-reactivity against a panel of human nuclear hormone receptors including PPARdelta. Compound 2 demonstrated an excellent pharmacological and safety profile in preclinical studies and thus was chosen as a development candidate for the treatment of atherosclerosis and dyslipidemia. The X-ray cocrystal structures of the early lead compound 12 and compound 2 in complex with PPARalpha ligand binding domain (LBD) were determined. The role of the crystal structure of compound 12 with PPARalpha in the development of the SAR that ultimately resulted in the discovery of compound 2 is discussed.
Subject(s)
Drug Discovery , Glycine/analogs & derivatives , Oxazoles/chemistry , Oxazoles/pharmacology , PPAR alpha/agonists , Animals , Cell Line , Cricetinae , Crystallography, X-Ray , Drug-Related Side Effects and Adverse Reactions , Glycine/chemical synthesis , Glycine/chemistry , Glycine/pharmacology , Glycine/toxicity , Humans , Male , Mice , Models, Molecular , Oxazoles/chemical synthesis , Oxazoles/toxicity , PPAR alpha/chemistry , PPAR alpha/genetics , Protein Structure, Tertiary , Substrate Specificity , Transcriptional Activation/drug effectsABSTRACT
A novel series of potent dual agonists of PPARalpha and PPARgamma, the alkoxybenzylglycines, was identified and explored using a solution-phase library approach. The synthesis and structure-activity relationships of this series of dual PPARalpha/gamma agonists are described.
Subject(s)
Glycine/analogs & derivatives , Glycine/pharmacology , PPAR alpha/agonists , PPAR gamma/agonists , Amino Acids/chemistry , Amino Acids/pharmacology , Animals , Blood Glucose/drug effects , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Hypolipidemic Agents/chemistry , Hypolipidemic Agents/pharmacology , Mice , Mice, Inbred Strains , Structure-Activity RelationshipABSTRACT
Muraglitazar/BMS-298585 (2) has been identified as a non-thiazolidinedione PPAR alpha/gamma dual agonist that shows potent activity in vitro at human PPARalpha (EC(50) = 320 nM) and PPARgamma(EC(50) = 110 nM). Compound 2 shows excellent efficacy for lowering glucose, insulin, triglycerides, and free fatty acids in genetically obese, severely diabetic db/db mice and has a favorable ADME profile. Compound 2 is currently in clinical development for the treatment of type 2 diabetes and dyslipidemia.
