α-alkyl substituted pirinixic acid derivatives as potent dual agonists of the peroxisome proliferator activated receptor alpha and gamma
α-alkyl substituted pirinixic acid derivatives as potent dual agonists of the peroxisome proliferator activated receptor alpha and gamma
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DOI：
10.1002/ardp.200700209
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发表时间：
2008-03-01
影响因子：
5.1
通讯作者：
Schubert-Zsilavecz, Manfred
中科院分区：
文献类型：
--
作者：
Rau, Oliver;Syha, Yvonne;Schubert-Zsilavecz, Manfred
过氧化物酶体增殖物激活受体（Peroxisome proliferator-activated receptor，PPAR）是一种核受体，在维持机体能量平衡中起着重要作用。PPARalpha亚型的激活剂广泛用于治疗高脂血症，而PPARgamma亚型的激活剂在临床上用于治疗2型糖尿病。由于这两种疾病经常相关，用一种药物同时激活PPARa和PPARy的联合治疗似乎是值得的。从作为中等活性的双重PPARa/γ激动剂的吡啉酸开始，我们通过用脂肪族链取代α-位来改善对人PPARa和PPARy的效力。在链长分别为4和6个碳时达到最大效果，分别导致PPAR α和PPAR γ的活性诱导因子分别为36和18。
Peroxisome proliferator-activated receptors (PPAR) are nuclear receptors, playing a pivotal role in energy homeostasis. Activators of the PPAR alpha subtype are in widespread use for the treatment of hyperlipidemia, while activators of the PPAR gamma subtype are in clinical use for the treatment of type-2 diabetes. Since both of these diseases are frequently associated, the combined treatment with one drug simultaneously activating PPARa and PPAR gamma seems worthwhile. Starting with pirinixic acid, which is a moderately active dual PPAR alpha/gamma agonist, we improved potency at the human PPARa and PPAR gamma by substituting the a-position with an aliphatic chain. The maximal effect was achieved at a chain length of four and six carbons, respectively, leading to an activity induction by a factor of 36 for PPAR alpha and 18 for PPAR gamma, respectively.