Modification at the acidic domain of RXR agonists has little effect on permissive RXR-heterodimer activation
Modification at the acidic domain of RXR agonists has little effect on permissive RXR-heterodimer activation
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DOI：
10.1016/j.bmcl.2010.07.012
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发表时间：
2010-09-01
影响因子：
2.7
通讯作者：
Kakuta, Hiroki
中科院分区：
文献类型：
--
作者：
Fujii, Shuji;Ohsawa, Fuminori;Kakuta, Hiroki
维甲酸X受体(RXRs)与其他核受体如过氧化物酶体增殖物激活受体(PPARs)或肝X受体(LXRs)起同源或异源二聚体的作用，PPARs是治疗高脂血症和2型糖尿病的靶点，LXRs参与糖脂代谢。PPAR/RXR或LXR/RXR被称为许可的RXR-异源二聚体，因为它们只被RXR激动剂激活。有趣的是，RXR-异二聚体的激活模式因RXR激动剂的结构而异，但其构效关系尚未见报道。在这里，我们表明，修饰或取代RXR激动剂酸性区域的羧基对RXR-异二聚体的激活几乎没有影响。从常见的溴代中间体7合成了膦酸(9)、四氮唑(10)和异羟肟酸(12)类似物。除9外，这些化合物在1-10mU的浓度范围内都表现出RXR全激动剂活性。对PPARγ/RXRα和LXRα/RXRα的激动剂活性顺序与RXR相同，即11>；10>；12。这些结果将有助于开发生物利用度更高的RXR激动剂。(C)2010爱思唯尔有限公司。保留所有权利。
Retinoid X receptors (RXRs) function as homo-or heterodimers with other nuclear receptors, such as peroxisome proliferator-activated receptors (PPARs), which are targets for treatment of hyperlipidemia and type 2 diabetes, or liver X receptors (LXRs), which are involved in glucose/lipid metabolism. PPAR/RXR or LXR/RXR are known as permissive RXR-heterodimers because they are activated by RXR agonists alone. Interestingly, the pattern of RXR-heterodimer activation is different depending on the RXR agonist structure, but the structure-activity relationship has not been reported. Here we show that modification or replacement of the carboxyl group in the acidic domain of RXR agonists has little or no effect on permissive RXR-heterodimer activation. Phosphonic acid (9), tetrazole (10), and hydroxamic acid (12) analogues were synthesized from the common bromo intermediate 7. Except for 9, these compounds showed RXR full-agonistic activities in the concentration range of 1-10 mu M. The order of agonistic activity toward both PPAR gamma/RXR alpha and LXR alpha/RXR alpha was the same as it was for RXR, that is, 11 > 10 > 12. These results should be useful for the development of RXR agonists with improved bioavailability. (C) 2010 Elsevier Ltd. All rights reserved.