Pingali Harikishore, Jain Mukul, Shah Shailesh, Patil Pravin, Makadia Pankaj, Zaware Pandurang, Sairam Kalapatapu V V M, Jamili Jeevankumar, Goel Ashish, Patel Megha, Patel Pankaj
Zydus Research Centre, Sarkhej-Bavla N.H. No. 8A, Moraiya, Ahmedabad, Gujarat 382210, India.
Bioorg Med Chem Lett. 2008 Dec 15;18(24):6471-5. doi: 10.1016/j.bmcl.2008.10.062. Epub 2008 Oct 17.
Oxazole containing glycine and oximinobutyric acid derivatives were synthesized as PPARalpha agonists by incorporating polymethylene spacer as a replacement of commonly used phenylene group that connects the acidic head with lipophilic tail. Compound 13a was found to be a selective and potent PPARalpha agonist. Further 1,3-dioxane-2-carboxylic acid derivative 20 was synthesized by replacing the tetramethylene spacer of NS-220, a selective PPARalpha agonist with phenylene group and found to exhibit PPARalpha/gamma dual agonism. These results suggest that compounds possessing polymethylene spacer between pharmacophore and lipophilic tail exhibit predominantly PPARalpha agonism whereas those with an aromatic phenylene spacer shows PPARalpha/gamma dual agonism.
通过引入聚亚甲基间隔基来替代连接酸性头部与亲脂性尾部的常用亚苯基，合成了含恶唑的甘氨酸和肟基丁酸衍生物作为过氧化物酶体增殖物激活受体α（PPARα）激动剂。发现化合物13a是一种选择性强效PPARα激动剂。进一步地，通过用亚苯基取代选择性PPARα激动剂NS - 220的四亚甲基间隔基，合成了1,3 - 二恶烷 - 2 - 羧酸衍生物20，发现其具有PPARα/γ双重激动作用。这些结果表明，在药效基团和亲脂性尾部之间具有聚亚甲基间隔基的化合物主要表现出PPARα激动作用，而具有芳香族亚苯基间隔基的化合物则表现出PPARα/γ双重激动作用。
