ABSTRACT
A series of phenoxyacetic acids as subtype selective and potent hPPARδ partial agonists is described. Many analogues were readily accessible via a single solution-phase synthetic route which resulted in the rapid identification of key structure-activity relationships (SAR), and the discovery of two potent exemplars which were further evaluated in vivo. Details of the SAR, optimization, and in vivo efficacy of this series are presented herein.
Subject(s)
Acetates/chemistry , PPAR delta/agonists , Acetates/chemical synthesis , Acetates/pharmacokinetics , Animals , Binding Sites , Crystallography, X-Ray , Humans , Male , Mice , Microsomes, Liver/metabolism , PPAR delta/metabolism , Rats , Structure-Activity RelationshipABSTRACT
We report the synthesis and biological activity of a new series of small molecule agonists of the human Peroxisome Proliferator-Activated Receptor delta (PPARdelta). Several hits were identified from our original libraries containing lipophilic carboxylic acids. Optimization of these hits by structure-guided design led to 7k (GW501516) and 7l (GW0742), which shows an EC(50) of 1.1 nM against PPARdelta with 1000-fold selectivity over the other human subtypes.
Subject(s)
Receptors, Cytoplasmic and Nuclear/agonists , Thiazoles/chemical synthesis , Transcription Factors/agonists , Animals , Cells, Cultured , Combinatorial Chemistry Techniques , Humans , Mice , Radioligand Assay , Structure-Activity Relationship , Thiazoles/chemistry , Thiazoles/pharmacology , Transcriptional ActivationABSTRACT
A solid-phase synthesis of substituted benzopyranoisoxazoles is described. The six-step synthesis features a novel method of generating nitrile oxides on a polymer support followed by an intramolecular 1,3-dipolar cycloaddition with a tethered alkyne for assembly of the benzopyranoisoxazole scaffold. Furthermore, the utilization of single-bead attenuated total reflectance Fourier transform infrared (ATR-IR) microspectroscopy as an essential analytical tool for reaction optimization is highlighted.
