Identification of Darmstoff analogs as selective agonists and antagonists of lysophosphatidic acid receptors
Identification of Darmstoff analogs as selective agonists and antagonists of lysophosphatidic acid receptors
复制标题
DOI：
10.1016/j.bmcl.2005.08.096
复制
发表时间：
2006-01-15
影响因子：
2.7
通讯作者：
Miller, DD
中科院分区：
文献类型：
--
作者：
Gududuru, V;Zeng, K;Miller, DD
Darmstoff 描述了一系列刺激肠道平滑肌的乙缩醛磷脂酸，最初是在 50 多年前从受刺激肠道的浴液中分离和表征的。尽管结构和生物学特征相似，但达姆斯托夫类似物之前并未被视为潜在的 LPA 模拟物。在这里，我们报告了一种合成达姆斯托夫类似物钾盐的简便方法。为了了解立体化学对溶血磷脂酸模拟活性的影响，从手性甘油酸甲酯开始合成选定的达姆斯托夫类似物的光学纯立体异构体。评估了每种 Darmstoff 类似物的亚型特异性 LPA 受体激动剂/拮抗剂活性、PPAR γ 激活和自分泌运动因子抑制。从这项研究中，我们鉴定出化合物 12 是 LPA(1-3) 受体的泛拮抗剂和几种泛激动剂。在脂质链中引入芳环（例如类似物 22）可产生亚型特异性 LPA(3) 激动剂，EC50 为 692 nM。有趣的是，无论其 LPA(1/2/3) 配体特性如何，所有达姆斯托夫类似物都测试了激活的 PPAR gamma。然而，这些化合物是自分泌运动因子的弱抑制剂。结果表明达姆斯托夫类似物构成了一类新型的溶血磷脂酸模拟物。 (c) 2005 Elsevier Ltd. 保留所有权利。
Darmstoff describes a family of gut smooth muscle-stimulating acetal phosphatidic acids initially isolated and characterized from the bath fluid of stimulated gut over 50 years ago. Despite similar structural and biological profiles, Darmstoff analogs have not previously been examined as potential LPA mimetics. Here, we report a facile method for the synthesis of potassium salts of Darmstoff analogs. To understand the effect of stereochemistry on lysophosphatidic acid mimetic activity, synthesis of optically pure stereoisomers of selected Darmstoff analogs was achieved starting with chiral methyl glycerates. Each Darmstoff analog was evaluated for subtype-specific LPA receptor agonist/antagonist activity, PPAR gamma activation, and autotaxin inhibition. From this study we identified compound 12 as a pan-antagonist and several pan-agonists for the LPA(1-3) receptors. Introduction of an aromatic ring in the lipid chain such as analog 22 produced a subtype-specific LPA(3) agonist with an EC50 of 692 nM. Interestingly, regardless of their LPA(1/2/3) ligand properties all of the Darmstoff analogs tested activated PPAR gamma. However, these compounds are weak inhibitors of autotaxin. The results indicate that Darmstoff analogs constitute a novel class of lysophosphatidic acid mimetics. (c) 2005 Elsevier Ltd. All rights reserved.