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Benzimidazolones: a new class of selective peroxisome proliferator-activated receptor γ (PPARγ) modulators.
Benzimidazolones: a new class of selective peroxisome proliferator-activated receptor γ (PPARγ) modulators.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2011 Dec 22; Vol. 54 (24), pp. 8541-54. Date of Electronic Publication: 2011 Nov 28. - Publication Year :
- 2011
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Abstract
- A series of benzimidazolone carboxylic acids and oxazolidinediones were designed and synthesized in search of selective PPARγ modulators (SPPARγMs) as potential therapeutic agents for the treatment of type II diabetes mellitus (T2DM) with improved safety profiles relative to rosiglitazone and pioglitazone, the currently marketed PPARγ full agonist drugs. Structure-activity relationships of these potent and highly selective SPPARγMs were studied with a focus on their unique profiles as partial agonists or modulators. A variety of methods, such as X-ray crystallographic analysis, PPARγ transactivation coactivator profiling, gene expression profiling, and mutagenesis studies, were employed to reveal the differential interactions of these new analogues with PPARγ receptor in comparison to full agonists. In rodent models of T2DM, benzimidazolone analogues such as (5R)-5-(3-{[3-(5-methoxybenzisoxazol-3-yl)benzimidazol-1-yl]methyl}phenyl)-5-methyloxazolidinedione (51) demonstrated efficacy equivalent to that of rosiglitazone. Side effects, such as fluid retention and heart weight gain associated with PPARγ full agonists, were diminished with 51 in comparison to rosiglitazone based on studies in two independent animal models.
- Subjects :
- Animals
Benzimidazoles chemistry
Benzimidazoles pharmacology
Binding Sites
COS Cells
Chlorocebus aethiops
Crystallography, X-Ray
Diabetes Mellitus, Type 2 drug therapy
Dimethadione chemical synthesis
Dimethadione chemistry
Dimethadione pharmacology
Drug Partial Agonism
Gene Expression Profiling
Humans
Hypoglycemic Agents chemistry
Hypoglycemic Agents pharmacology
Male
Mice
Models, Molecular
Mutagenesis
Nuclear Receptor Coactivators metabolism
Oxazoles chemical synthesis
Oxazoles chemistry
Oxazoles pharmacology
PPAR gamma agonists
PPAR gamma genetics
Pioglitazone
Protein Conformation
Rats
Rats, Zucker
Rosiglitazone
Structure-Activity Relationship
Thiazolidinediones chemistry
Thiazolidinediones pharmacology
Transcriptional Activation
Benzimidazoles chemical synthesis
Dimethadione analogs & derivatives
Hypoglycemic Agents chemical synthesis
PPAR gamma metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 54
- Issue :
- 24
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 22070604
- Full Text :
- https://doi.org/10.1021/jm201061j