ABSTRACT
Propionic acid derivative 8, which was designed and synthesized based on putative pharmacophores of known PPARgamma- and PPARalpha-selective compounds, exhibits potent dual PPARalpha/gamma agonist activity as demonstrated by in vitro binding and dose overlap in the newly introduced EOB mouse model for glucose lowering and lipid/cholesterol homeostasis.
Subject(s)
Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/pharmacology , Propionates/chemical synthesis , Propionates/pharmacology , Receptors, Cytoplasmic and Nuclear/agonists , Transcription Factors/agonists , Animals , Blood Glucose/metabolism , Cholesterol, HDL/blood , Diabetes Mellitus/blood , Diabetes Mellitus/drug therapy , Diabetes Mellitus/genetics , Diabetes Mellitus, Type 2/drug therapy , Drug Design , Mice , Mice, Inbred Strains , Receptors, Cytoplasmic and Nuclear/genetics , Transcription Factors/genetics , Triglycerides/bloodABSTRACT
A library of potential agonists and antagonists for adrenergic receptors was prepared using high-throughput solution-phase parallel synthesis. Traditional solution-phase reductive amination reactions followed by rapid purification by ion exchange chromatography yielded products with near-analytical purity. An array of ketones and amines, arranged in an 8 x 12 matrix, were combined to form 96 individual compounds.
