title: Design and synthesis of alpha-aryloxy-alpha-methylhydrocinnamic acids: a novel class of dual peroxisome proliferator-activated receptor alpha/gamma agonists.
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.
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly & Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA. xu_yanping@lilly.com
authors.forename: Yanping
authors.initials: Y
authors.lastname: Xu
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Rito
authors.forename: Garret J
authors.initials: GJ
authors.lastname: Etgen
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Ardecky
authors.forename: James S
authors.initials: JS
authors.lastname: Bean
authors.forename: William R
authors.initials: WR
authors.lastname: Bensch
authors.forename: Jacob R
authors.initials: JR
authors.lastname: Bosley
authors.forename: Carol L
authors.initials: CL
authors.lastname: Broderick
authors.forename: Dawn A
authors.initials: DA
authors.lastname: Brooks
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Dominianni
authors.forename: Patric J
authors.initials: PJ
authors.lastname: Hahn
authors.forename: Sha
authors.initials: S
authors.lastname: Liu
authors.forename: Dale E
authors.initials: DE
authors.lastname: Mais
authors.forename: Chahrzad
authors.initials: C
authors.lastname: Montrose-Rafizadeh
authors.forename: Kathy M
authors.initials: KM
authors.lastname: Ogilvie
authors.forename: Brian A
authors.initials: BA
authors.lastname: Oldham
authors.forename: Mary
authors.initials: M
authors.lastname: Peters
authors.forename: Deepa K
authors.initials: DK
authors.lastname: Rungta
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Shuker
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Stephenson
authors.forename: Allie E
authors.initials: AE
authors.lastname: Tripp
authors.forename: Sarah B
authors.initials: SB
authors.lastname: Wilson
authors.forename: Leonard L
authors.initials: LL
authors.lastname: Winneroski
authors.forename: Richard
authors.initials: R
authors.lastname: Zink
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Kauffman
authors.forename: James R
authors.initials: JR
authors.lastname: McCarthy
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D005260:Female; D006801:Humans; D006949:Hyperlipidemias / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000960:Hypolipidemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010666:Phenylpropionates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011924:Rats, Zucker; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014157:Transcription Factors / Q000819:agonists*
chemical_list: C486784:2-methyl-3-(4-(2-(5-methyl-2-thiophen-2-yloxazol-4-yl)ethoxy)phenyl)-2-phenoxypropionic acid; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D010666:Phenylpropionates; D018160:Receptors, Cytoplasmic and Nuclear; D013876:Thiophenes; D014157:Transcription Factors