title: Benzimidazolones: a new class of selective peroxisome proliferator-activated receptor γ (PPARγ) modulators.
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.
authors: Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, United States. weiguo_liu@merck.com
authors: Weiguo
authors: W
authors: Liu
authors: Fiona
authors: F
authors: Lau
authors: Kun
authors: K
authors: Liu
authors: Harold B
authors: HB
authors: Wood
authors: Gaochao
authors: G
authors: Zhou
authors: Yuli
authors: Y
authors: Chen
authors: Ying
authors: Y
authors: Li
authors: Taro E
authors: TE
authors: Akiyama
authors: Gino
authors: G
authors: Castriota
authors: Monica
authors: M
authors: Einstein
authors: Chualin
authors: C
authors: Wang
authors: Margaret E
authors: ME
authors: McCann
authors: Thomas W
authors: TW
authors: Doebber
authors: Margaret
authors: M
authors: Wu
authors: Ching H
authors: CH
authors: Chang
authors: Lesley
authors: L
authors: McNamara
authors: Brian
authors: B
authors: McKeever
authors: Ralph T
authors: RT
authors: Mosley
authors: Joel P
authors: JP
authors: Berger
authors: Peter T
authors: PT
authors: Meinke
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D019556:COS Cells; D002522:Chlorocebus aethiops; D018360:Crystallography, X-Ray; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004114:Dimethadione / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D054333:Drug Partial Agonism; D020869:Gene Expression Profiling; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D051379:Mice; D008958:Models, Molecular; D016296:Mutagenesis; D056918:Nuclear Receptor Coactivators / Q000378:metabolism; D010080:Oxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D000077205:Pioglitazone; D011487:Protein Conformation; D051381:Rats; D011924:Rats, Zucker; D000077154:Rosiglitazone; D013329:Structure-Activity Relationship; D045162:Thiazolidinediones / Q000737:chemistry / Q000494:pharmacology; D015533:Transcriptional Activation
chemical_list: C570539:5-(3-((3-(5-methoxybenzisoxazol-3-yl)benzimidazol-1-yl)methyl)phenyl)-5-methyloxazolidinedione; D001562:Benzimidazoles; D007004:Hypoglycemic Agents; D056918:Nuclear Receptor Coactivators; D010080:Oxazoles; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D004114:Dimethadione; D000077205:Pioglitazone