title: Identification of diaryl ether-based ligands for estrogen-related receptor α as potential antidiabetic agents.
abstract: Estrogen-related receptor α (ERRα) is an orphan nuclear receptor that has been functionally implicated in the regulation of energy homeostasis. Herein is described the development of diaryl ether based thiazolidenediones, which function as selective ligands against this receptor. Series optimization provided several potent analogues that inhibit the recruitment of a coactivator peptide fragment in in vitro biochemical assays (IC(50) < 150 nM) and cellular two-hybrid reporter assays against the ligand binding domain (IC(50) = 1-5 μM). A cocrystal structure of the ligand-binding domain of ERRα with lead compound 29 revealed the presence of a covalent interaction between the protein and ligand, which has been shown to be reversible. In diet-induced murine models of obesity and in an overt diabetic rat model, oral administration of 29 normalized insulin and circulating triglyceride levels, improved insulin sensitivity, and was body weight neutral. This provides the first demonstration of functional activities of an ERRα ligand in metabolic animal models.
authors.affiliation: Johnson & Johnson Pharmaceutical Research and Development, Welsh and McKean Roads, Spring House, PA 19477-0776, USA.
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Patch
authors.forename: Lily L
authors.initials: LL
authors.lastname: Searle
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Kim
authors.forename: Debyendu
authors.initials: D
authors.lastname: De
authors.forename: Xizhen
authors.initials: X
authors.lastname: Zhu
authors.forename: Hossein B
authors.initials: HB
authors.lastname: Askari
authors.forename: John C
authors.initials: JC
authors.lastname: O'Neill
authors.forename: Marta C
authors.initials: MC
authors.lastname: Abad
authors.forename: Dionisios
authors.initials: D
authors.lastname: Rentzeperis
authors.forename: Jianying
authors.initials: J
authors.lastname: Liu
authors.forename: Michael
authors.initials: M
authors.lastname: Kemmerer
authors.forename: Ling
authors.initials: L
authors.lastname: Lin
authors.forename: Jyotsna
authors.initials: J
authors.lastname: Kasturi
authors.forename: John G
authors.initials: JG
authors.lastname: Geisler
authors.forename: James M
authors.initials: JM
authors.lastname: Lenhard
authors.forename: Mark R
authors.initials: MR
authors.lastname: Player
authors.forename: Micheal D
authors.initials: MD
authors.lastname: Gaul
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001667:Binding, Competitive; D001682:Biological Availability; D018360:Crystallography, X-Ray; D003920:Diabetes Mellitus / Q000188:drug therapy; D004285:Dogs; D004987:Ethers / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008024:Ligands; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D015394:Molecular Structure; D009765:Obesity / Q000188:drug therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D045162:Thiazolidinediones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D014280:Triglycerides / Q000097:blood; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D004987:Ethers; D007004:Hypoglycemic Agents; D007328:Insulin; D008024:Ligands; D011960:Receptors, Estrogen; D045162:Thiazolidinediones; D014280:Triglycerides; D000097983:ERRalpha Estrogen-Related Receptor; C575631:4-(4-(2,4-dioxothiazolidin-5-ylidenemethyl)-2-methoxyphenoxy)-3-trifluoromethylbenzonitrile