title: Design and synthesis of novel and potent amide linked PPARgamma/delta dual agonists.
abstract: A series of potent amide linked PPARgamma/delta dual agonists (1a) has been discovered through rational design. In the ZDF rat model of type 2 diabetes, compound (R)-3-[4-(3-{1-[(5-chloro-1,3-dimethyl-1H-indole-2-carbonyl)-amino]-ethyl}-5-fluoro-phenoxy)-2-ethyl-phenyl]-propionic acid (42) from this series has demonstrated glucose lowering efficacy comparable to the marketed PPARgamma agonist rosiglitazone with less weight gain.
authors.affiliation: Eli Lilly and Company, Lilly Research Labs, Lilly Corporate Center, Indianapolis, IN 46285, USA. shi_qing@lilly.com
authors.forename: Qing
authors.initials: Q
authors.lastname: Shi
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Canada
authors.forename: Yanping
authors.initials: Y
authors.lastname: Xu
authors.forename: Alan M
authors.initials: AM
authors.lastname: Warshawsky
authors.forename: Garret J
authors.initials: GJ
authors.lastname: Etgen
authors.forename: Carol L
authors.initials: CL
authors.lastname: Broderick
authors.forename: Cathleen K
authors.initials: CK
authors.lastname: Clutinger
authors.forename: Lynnie A
authors.initials: LA
authors.lastname: Irwin
authors.forename: Michael E
authors.initials: ME
authors.lastname: Laurila
authors.forename: Chahrzad
authors.initials: C
authors.lastname: Montrose-Rafizadeh
authors.forename: Brian A
authors.initials: BA
authors.lastname: Oldham
authors.forename: Minmin
authors.initials: M
authors.lastname: Wang
authors.forename: Leonard L
authors.initials: LL
authors.lastname: Winneroski
authors.forename: Chaoyu
authors.initials: C
authors.lastname: Xie
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: York
authors.forename: Nathan P
authors.initials: NP
authors.lastname: Yumibe
authors.forename: Richard W
authors.initials: RW
authors.lastname: Zink
authors.forename: Nathan
authors.initials: N
authors.lastname: Mantlo
mesh_terms: D000577:Amides / Q000737:chemistry*; D000818:Animals; D020650:Combinatorial Chemistry Techniques; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004195:Disease Models, Animal; D015195:Drug Design; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D047494:PPAR delta / Q000819:agonists*; D047495:PPAR gamma / Q000819:agonists*; D051381:Rats
chemical_list: C526678:(R)-3-(4-(3-(1-((5-chloro-1,3-dimethyl-1H-indole-2-carbonyl)amino)ethyl)-5-fluoro-phenoxy)-2-ethylphenyl)propionic acid; D000577:Amides; D007211:Indoles; D047494:PPAR delta; D047495:PPAR gamma