Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 2 de 2
Filter
Add more filters










Database
Language
Publication year range
1.
Bioorg Med Chem Lett ; 14(24): 6113-6, 2004 Dec 20.
Article in English | MEDLINE | ID: mdl-15546740

ABSTRACT

To understand the species selectivity in a series of alpha-methyl-alpha-phenoxy carboxylic acid PPARalpha/gamma dual agonists (1-11), structure-based molecular modeling was carried out in the ligand binding pockets of both human and mouse PPARalpha. This study suggested that interaction of both 4-phenoxy and phenyloxazole substituents of these ligands with F272 and M279 in mouse PPARalpha leads to the species-specific divergence in ligand binding. Insights obtained in the molecular modeling studies of these key interactions resulted in the ability to convert a human-selective PPARalpha agonist to a human and mouse dual agonist within the same platform.


Subject(s)
Cinnamates/chemical synthesis , Models, Molecular , PPAR alpha/agonists , Animals , Cinnamates/chemistry , Cinnamates/pharmacology , Drug Design , Humans , Ligands , Mice , Molecular Structure , Species Specificity , Structure-Activity Relationship
2.
J Med Chem ; 47(10): 2422-5, 2004 May 06.
Article in English | MEDLINE | ID: mdl-15115385

ABSTRACT

The design and synthesis of the dual peroxisome proliferator activated receptor (PPAR) alpha/gamma agonist (S)-2-methyl-3-[4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)ethoxy]phenyl]-2-phenoxypropionic acid (2) for the treatment of type 2 diabetes and associated dyslipidemia are described. 2 possesses a potent dual hPPAR alpha/gamma agonist profile (IC(50) = 28 and 10 nM; EC(50) = 9 and 4 nM, respectively, for hPPARalpha and hPPARgamma). In preclinical models, 2 substantially improves insulin sensitivity and potently reverses diabetic hyperglycemia while significantly improving overall lipid homeostasis.


Subject(s)
Hypoglycemic Agents/chemical synthesis , Hypolipidemic Agents/chemical synthesis , Phenylpropionates/chemical synthesis , Receptors, Cytoplasmic and Nuclear/agonists , Thiophenes/chemical synthesis , Transcription Factors/agonists , Animals , Binding, Competitive , Cell Line , Diabetes Mellitus, Type 2/drug therapy , Female , Humans , Hyperlipidemias/drug therapy , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Hypolipidemic Agents/chemistry , Hypolipidemic Agents/pharmacology , Phenylpropionates/chemistry , Phenylpropionates/pharmacology , Radioligand Assay , Rats , Rats, Zucker , Stereoisomerism , Structure-Activity Relationship , Thiophenes/chemistry , Thiophenes/pharmacology
SELECTION OF CITATIONS
SEARCH DETAIL
...