3,4,5-Trisubstituted isoxazoles as novel PPARdelta agonists. Part 2.
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.
Epple
Robert
R
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
Azimioara
Mihai
M
Russo
Ross
R
Xie
Yongping
Y
Wang
Xing
X
Cow
Christopher
C
Wityak
John
J
Karanewsky
Don
D
Bursulaya
Badry
B
Kreusch
Andreas
A
Tuntland
Tove
T
Gerken
Andrea
A
Iskandar
Maya
M
Saez
Enrique
E
Martin Seidel
H
H
Tian
Shin-Shay
SS
D000818:Animals; D007555:Isoxazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D047494:PPAR delta / Q000819:agonists* / Q000737:chemistry*
D007555:Isoxazoles; D047494:PPAR delta