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Discovery of an oxybenzylglycine based peroxisome proliferator activated receptor alpha selective agonist 2-((3-((2-(4-chlorophenyl)-5-methyloxazol-4-yl)methoxy)benzyl)(methoxycarbonyl)amino)acetic acid (BMS-687453)
- Source :
- Journal of medicinal chemistry. 53(7)
- Publication Year :
- 2010
-
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.
- Subjects :
- Agonist
Male
Models, Molecular
Transcriptional Activation
Drug-Related Side Effects and Adverse Reactions
Stereochemistry
medicine.drug_class
Glycine
Peroxisome proliferator-activated receptor
Crystallography, X-Ray
Cell Line
Substrate Specificity
Transactivation
chemistry.chemical_compound
Mice
Cricetinae
Drug Discovery
medicine
Animals
Humans
PPAR alpha
Receptor
Oxazoles
chemistry.chemical_classification
Protein Structure, Tertiary
chemistry
Nuclear receptor
Biochemistry
Hormone receptor
Molecular Medicine
Peroxisome proliferator-activated receptor alpha
Lead compound
Subjects
Details
- ISSN :
- 15204804
- Volume :
- 53
- Issue :
- 7
- Database :
- OpenAIRE
- Journal :
- Journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....bb4707731fd9751cfe48ed0a665b764c