title: Discovery of azetidinone acids as conformationally-constrained dual PPARalpha/gamma agonists.
abstract: A novel class of azetidinone acid-derived dual PPARalpha/gamma agonists has been synthesized for the treatment of diabetes and dyslipidemia. The preferred stereochemistry in this series for binding and functional agonist activity against both PPARalpha and PPARgamma receptors was shown to be 3S,4S. Synthesis, in vitro and in vivo activities of compounds in this series are described. A high-yielding method for N-arylation of azetidinone esters is also described.
authors.affiliation: Metabolic Diseases Chemistry, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Pratik
authors.initials: P
authors.lastname: Devasthale
authors.forename: Dennis
authors.initials: D
authors.lastname: Farrelly
authors.forename: Liqun
authors.initials: L
authors.lastname: Gu
authors.forename: Thomas
authors.initials: T
authors.lastname: Harrity
authors.forename: Michael
authors.initials: M
authors.lastname: Cap
authors.forename: Cuixia
authors.initials: C
authors.lastname: Chu
authors.forename: Lori
authors.initials: L
authors.lastname: Kunselman
authors.forename: Nathan
authors.initials: N
authors.lastname: Morgan
authors.forename: Randy
authors.initials: R
authors.lastname: Ponticiello
authors.forename: Rachel
authors.initials: R
authors.lastname: Zebo
authors.forename: Litao
authors.initials: L
authors.lastname: Zhang
authors.forename: Kenneth
authors.initials: K
authors.lastname: Locke
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lippy
authors.forename: Kevin
authors.initials: K
authors.lastname: O'Malley
authors.forename: Vinayak
authors.initials: V
authors.lastname: Hosagrahara
authors.forename: Lisa
authors.initials: L
authors.lastname: Zhang
authors.forename: Pathanjali
authors.initials: P
authors.lastname: Kadiyala
authors.forename: Chiehying
authors.initials: C
authors.lastname: Chang
authors.forename: Jodi
authors.initials: J
authors.lastname: Muckelbauer
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Doweyko
authors.forename: Robert
authors.initials: R
authors.lastname: Zahler
authors.forename: Denis
authors.initials: D
authors.lastname: Ryono
authors.forename: Narayanan
authors.initials: N
authors.lastname: Hariharan
authors.forename: Peter T W
authors.initials: PT
authors.lastname: Cheng
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001384:Azetidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001682:Biological Availability; D003300:Copper / Q000494:pharmacology; D018360:Crystallography, X-Ray; D065607:Cytochrome P-450 Enzyme Inhibitors; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D050171:Dyslipidemias / Q000188:drug therapy; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D015394:Molecular Structure; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D011487:Protein Conformation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014280:Triglycerides / Q000097:blood
chemical_list: C116379:2-azetidinone; D001384:Azetidines; D065607:Cytochrome P-450 Enzyme Inhibitors; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D047493:PPAR alpha; D047495:PPAR gamma; D014280:Triglycerides; D003300:Copper; D005947:Glucose