Author/Authors :
Lan Shen، نويسنده , , Yan Zhang، نويسنده , , Aihua Wang، نويسنده , , Ellen Sieber-McMaster، نويسنده , , Xiaoli Chen، نويسنده , , Patricia Pelton، نويسنده , , June Z. Xu، نويسنده , , Maria Yang، نويسنده , , Peifang Zhu، نويسنده , , Lubing Zhou، نويسنده , , Michael Reuman، نويسنده , , Zhiyong Hu، نويسنده , , Ronald Russell، نويسنده , , Alan C. Gibbs، نويسنده , , Hamish Ross، نويسنده , , Keith Demarest، نويسنده , , William V. Murray، نويسنده , , Gee-Hong Kuo، نويسنده ,
Abstract :
Replacement of the methyl-thiazole moiety of GW501516 (a PPARδ selective agonist) with [1,2,4]thiadiazole gave compound 21 which unexpectedly displayed submicromolar potency as a partial agonist at PPARα in addition to the high potency at PPARδ. A structure–activity relationships study of 21 resulted in the identification of 40 as a potent and selective PPARα/δ dual agonist. Compound 40 and its close analogs represent a new series of PPARα/δ dual agonists. The high potency, high selectivity, significant gene induction, excellent PK profiles, low P450 inhibition or induction, and good in vivo efficacy in four animal models support 40 being selected as a pre-clinical study candidate, and may render 40 as a valuable pharmacological tool in elucidating the complex roles of PPARα/δ dual agonists, and the potential usage for the treatment of metabolic syndrome.
Keywords :
Thiadiazole , nuclear receptor , Metabolic syndrome , Gene induction