Synthesis and Identification of [1,2,4]Thiadiazole Derivatives as a New Series of Potent and Orally Active Dual Agonists of Peroxisome Proliferator-Activated Receptors 
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- 作者：Lan Shen ; Yan Zhang ; Aihua Wang ; Ellen Sieber-McMaster ; Xiaoli Chen ; Patricia Pelton ; Jun Z. Xu ; Maria Yang ; Peifang Zhu ; Lubing Zhou ; Michael Reuman ; Zhiyong Hu ; Ronald Russell ; Alan C. Gibbs ; Hamish
- 刊名：Journal of Medicinal Chemistry
- 出版年：2007
- 出版时间：August 9, 2007
- 年：2007
- 卷：50
- 期：16
- 页码：3954 - 3963
- 全文大小：311K
- 年卷期：v.50,no.16(August 9, 2007)
- ISSN：1520-4804
文摘
Cardiovascular disease is the most common cause of morbidity and mortality in developed nations. Toeffectively target dyslipidemia to reduce the risk of cardiovascular disease, it may be beneficial to activatethe peroxisome proliferator-activated receptors (PPARs) PPAR
and PPAR
simultaneously through a singlemolecule. Replacement of the methylthiazole of 5 (the PPAR selective agonist) with [1,2,4]thiadiazolegave compound 13, which unexpectedly displayed submicromolar potency as a partial agonist at PPAR inaddition to the high potency at PPAR. Optimization of 13 led to the identification of 24 as a potent andselective PPAR/ dual agonist. Compound 24 and its close analogs represent a new series of PPAR/dual agonists. The high potency, significant gene induction, excellent PK profiles, and good in vivo efficaciesin three animal models may render compound 24 as a valuable pharmacological tool in elucidating thecomplex roles of PPAR/ dual agonists and as a potential treatment of the metabolic syndrome.
and PPAR simultaneously through a singlemolecule. Replacement of the methylthiazole of 5 (the PPAR selective agonist) with [1,2,4]thiadiazolegave compound 13, which unexpectedly displayed submicromolar potency as a partial agonist at PPAR inaddition to the high potency at PPAR. Optimization of 13 led to the identification of 24 as a potent andselective PPAR/ dual agonist. Compound 24 and its close analogs represent a new series of PPAR/dual agonists. The high potency, significant gene induction, excellent PK profiles, and good in vivo efficaciesin three animal models may render compound 24 as a valuable pharmacological tool in elucidating thecomplex roles of PPAR/ dual agonists and as a potential treatment of the metabolic syndrome.