title: 3,4,5-Trisubstituted isoxazoles as novel PPARdelta agonists. Part 2.
abstract: A series of PPARdelta-selective agonists was investigated and optimized for a favorable in vivo pharmacokinetic profile. Isoxazole LCI765 (17d) was found to be a potent and selective PPARdelta agonist with good in vivo PK properties in mouse (C(max)=5.1 microM, t(1/2)=3.1 h). LCI765 regulated expression of genes involved in energy homeostasis in relevant tissues when dosed orally in C57BL6 mice. A co-crystal structure of compound LCI765 and the LBD of PPARdelta is discussed.
authors.affiliation: Department of Medicinal Chemistry, The Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA. repple@gnf.org
authors.forename: Robert
authors.initials: R
authors.lastname: Epple
authors.forename: Mihai
authors.initials: M
authors.lastname: Azimioara
authors.forename: Ross
authors.initials: R
authors.lastname: Russo
authors.forename: Yongping
authors.initials: Y
authors.lastname: Xie
authors.forename: Xing
authors.initials: X
authors.lastname: Wang
authors.forename: Christopher
authors.initials: C
authors.lastname: Cow
authors.forename: John
authors.initials: J
authors.lastname: Wityak
authors.forename: Don
authors.initials: D
authors.lastname: Karanewsky
authors.forename: Badry
authors.initials: B
authors.lastname: Bursulaya
authors.forename: Andreas
authors.initials: A
authors.lastname: Kreusch
authors.forename: Tove
authors.initials: T
authors.lastname: Tuntland
authors.forename: Andrea
authors.initials: A
authors.lastname: Gerken
authors.forename: Maya
authors.initials: M
authors.lastname: Iskandar
authors.forename: Enrique
authors.initials: E
authors.lastname: Saez
authors.forename: H
authors.initials: H
authors.lastname: Martin Seidel
authors.forename: Shin-Shay
authors.initials: SS
authors.lastname: Tian
mesh_terms: D000818:Animals; D007555:Isoxazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D047494:PPAR delta / Q000819:agonists* / Q000737:chemistry*
chemical_list: D007555:Isoxazoles; D047494:PPAR delta