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

The optimization of an isoxazole series to the potent, selective, and bioavailable PPARδ agonist LCI765 is reported. A co-crystal structure and in vivo properties of LCI765 are discussed. 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 = 5.1 μM, 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 PPARδ is discussed.