| Autor: |
Shen L; Drug Discovery Division, Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Cedarbrook Corporate Center, 8 Clarke Drive, Cranbury, NJ 08512, USA., Zhang Y, Wang A, Sieber-McMaster E, Chen X, Pelton P, Xu JZ, Yang M, Zhu P, Zhou L, Reuman M, Hu Z, Russell R, Gibbs AC, Ross H, Demarest K, Murray WV, Kuo GH |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 2007 Aug 09; Vol. 50 (16), pp. 3954-63. Date of Electronic Publication: 2007 Jul 04. |
| DOI: |
10.1021/jm070511x |
| Abstrakt: |
Cardiovascular disease is the most common cause of morbidity and mortality in developed nations. To effectively target dyslipidemia to reduce the risk of cardiovascular disease, it may be beneficial to activate the peroxisome proliferator-activated receptors (PPARs) PPARalpha and PPARdelta simultaneously through a single molecule. Replacement of the methylthiazole of 5 (the PPARdelta selective agonist) with [1,2,4]thiadiazole gave compound 13, which unexpectedly displayed submicromolar potency as a partial agonist at PPARalpha in addition to the high potency at PPARdelta. Optimization of 13 led to the identification of 24 as a potent and selective PPARalpha/delta dual agonist. Compound 24 and its close analogs represent a new series of PPARalpha/delta dual agonists. The high potency, significant gene induction, excellent PK profiles, and good in vivo efficacies in three animal models may render compound 24 as a valuable pharmacological tool in elucidating the complex roles of PPARalpha/delta dual agonists and as a potential treatment of the metabolic syndrome. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
|
