Synthesis and pharmacological evaluation of second-generation phosphatidic acid derivatives as lysophosphatidic acid receptor ligands
Synthesis and pharmacological evaluation of second-generation phosphatidic acid derivatives as lysophosphatidic acid receptor ligands
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DOI：
10.1016/j.bmcl.2005.10.031
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发表时间：
2006-02-01
影响因子：
2.7
通讯作者：
Miller, DD
中科院分区：
文献类型：
--
作者：
Durgam, GG;Tsukahara, R;Miller, DD
短链磷脂酸衍生物，二辛酰甘油焦磷酸（DGPP 8：0，1）和磷脂酸8：0（PA 8：0，2），以前被确定为亚型选择性LPA（1）和LPA（3）受体拮抗剂。最近，我们报道了在一系列脂肪醇磷酸酯（FAP）中用硫代磷酸酯取代磷酸酯头基，提高了LPA GPCR的激动剂和拮抗剂活性。在这里，我们报告的立体异构体的PA 8：0类似物的合成和它们的生物学评价在LPA GPCR，PPAR γ，和ATX。结果表明，LPA受体立体选择性地与甘油骨架修饰的配体相互作用。我们观察到二辛基PA 8：0化合物的完全立体特异性反应，其中（R）-异构体被发现是LPA GPCR的激动剂，（S）-异构体是LPA GPCR的拮抗剂。从这一系列中，我们鉴定出化合物13 b为最有效的LPA 3受体亚型选择性激动剂（EC 50 = 3 nM），和8b为有效和选择性的LPA 3受体拮抗剂（Ki = 5 nM）和ATX抑制剂（IC 50 = 600 nM）。丝氨酸二酰胺磷酸19 b被鉴定为LPA 3受体特异性拮抗剂，对LPA（1）、LPA（2）和PPAR γ无影响。(c)2005爱思唯尔有限公司保留所有权利。
Short-chain phosphatidic acid derivatives, dioctanoyl glycerol pyrophosphate (DGPP 8:0, 1) and phosphatidic acid 8:0 (PA 8:0, 2), were previously identified as subtype-selective LPA(1) and LPA(3) receptor antagonists. Recently, we reported that the replacement of the phosphate headgroup by thiophosphate in a series of fatty alcohol phosphates (FAP) improves agonist as well as antagonist activities at LPA GPCR. Here, we report the synthesis of stereoisomers of PA 8:0 analogs and their biological evaluation at LPA GPCR, PPAR gamma, and ATX. The results indicate that LPA receptors stereoselectively interact with glycerol backbone modified ligands. We observed entirely stereospecific responses by dioctyl PA 8:0 compounds, in which (R)-isomers were found to be agonists and (S)-isomers were antagonists of LPA GPCR. From this series, we identified compound 13b as the most potent LPA3 receptor subtype-selective agonist (EC50 = 3 nM), and 8b as a potent and selective LPA3 receptor antagonist (K-i = 5 nM) and inhibitor of ATX (IC50 = 600 nM). Serinediamide phosphate 19b was identified as an LPA3 receptor specific antagonist with no effect on LPA(1), LPA(2), and PPAR gamma. (c) 2005 Elsevier Ltd. All rights reserved.