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

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 (Cmax = 5.1 μM, t1/2 = 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.

Graphical abstractThe 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.Figure optionsDownload full-size imageDownload as PowerPoint slide