title: Design and synthesis of dual peroxisome proliferator-activated receptors gamma and delta agonists as novel euglycemic agents with a reduced weight gain profile.
abstract: The design and synthesis of the dual peroxisome proliferator-activated receptor (PPAR) gamma/delta agonist (R)-3-{4-[3-(4-chloro-2-phenoxy-phenoxy)-butoxy]-2-ethyl-phenyl}-propionic acid (20) for the treatment of type 2 diabetes and associated dyslipidemia is described. The compound possesses a potent dual hPPAR gamma/delta agonist profile (IC(50) = 19 nM/4 nM; EC(50) = 102 nM/6 nM for hPPARgamma and hPPARdelta, respectively). In preclinical models, the compound improves insulin sensitivity and reverses diabetic hyperglycemia with less weight gain at a given level of glucose control relative to rosiglitazone.
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: Garret J
authors.initials: GJ
authors.lastname: Etgen
authors.forename: Carol L
authors.initials: CL
authors.lastname: Broderick
authors.forename: Emily
authors.initials: E
authors.lastname: Canada
authors.forename: Isabel
authors.initials: I
authors.lastname: Gonzalez
authors.forename: Jason
authors.initials: J
authors.lastname: Lamar
authors.forename: Chahrzad
authors.initials: C
authors.lastname: Montrose-Rafizadeh
authors.forename: Brian A
authors.initials: BA
authors.lastname: Oldham
authors.forename: John J
authors.initials: JJ
authors.lastname: Osborne
authors.forename: Chaoyu
authors.initials: C
authors.lastname: Xie
authors.forename: Qing
authors.initials: Q
authors.lastname: Shi
authors.forename: Leonard L
authors.initials: LL
authors.lastname: Winneroski
authors.forename: Jeremy
authors.initials: J
authors.lastname: York
authors.forename: Nathan
authors.initials: N
authors.lastname: Yumibe
authors.forename: Richard
authors.initials: R
authors.lastname: Zink
authors.forename: Nathan
authors.initials: N
authors.lastname: Mantlo
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D015195:Drug Design; D050171:Dyslipidemias / Q000188:drug therapy; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D051379:Mice; D047493:PPAR alpha / Q000235:genetics; D047494:PPAR delta / Q000819:agonists*; D047495:PPAR gamma / Q000819:agonists*; D010647:Phenyl Ethers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010666:Phenylpropionates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D013237:Stereoisomerism; D015533:Transcriptional Activation; D015430:Weight Gain / Q000187:drug effects*
chemical_list: C514167:3-(4-(3-(4-chloro-2-phenoxyphenoxy)butoxy)-2-ethylphenyl)propionic acid; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D047493:PPAR alpha; D047494:PPAR delta; D047495:PPAR gamma; D010647:Phenyl Ethers; D010666:Phenylpropionates