3,4,5-Trisubstituted isoxazoles as novel PPARδ agonists. Part 2

Abstract: A series of PPARδ-selective agonists was investigated and optimized for a favorable in vivo pharmacokinetic profile. Isoxazole LCI765 (17d) was found to be a potent and selective PPARδ agonist with good in vivo PK properties in mouse (C max =5.1μM, t 1/2 =3.1h). 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 PPARδ is discussed. [Copyright &y& Elsevier]