Carboxy-substituted cinnamides:: A novel series of potent, orally active LTB4 receptor antagonists
Carboxy-substituted cinnamides:: A novel series of potent, orally active LTB4 receptor antagonists
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DOI：
10.1021/jm980540v
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发表时间：
1999-01-14
影响因子：
7.3
通讯作者：
Fitt, JJ
中科院分区：
文献类型：
--
作者：
Greenspan, PD;Fujimoto, RA;Fitt, JJ
研究了一系列羧基取代肉桂酸作为人细胞表面白三烯B-4 （LTB4）受体的拮抗剂。通过测量人中性粒细胞的[H-3]-LTB4位移来确定结合。受体拮抗剂通过功能测定证实，其测量Ca2+释放在人中性粒细胞的抑制。有效的拮抗剂被发现通过优化随机筛选击中，对-（α -甲基苯氧基）肉桂酸，具有低微摩尔活性。通过柔性系链将羧酸片段连接到肉桂酸苯基环上，实现了体外效价的大幅提高，从而鉴定出低纳摩尔效价的化合物。对苯氧基取代基的修饰，无论是通过苯氧基苯基上的邻位取代，还是通过用亚甲基或硫原子取代醚氧，都能产生同等或更强效的非手性拮抗剂。采用花生四烯酸诱导小鼠耳部炎症水肿模型，测定体外最强效化合物的口服活性。在口服给药17小时后，发现该系列中的几种化合物显著抑制该模型的水肿形成和髓过氧化物酶活性。该系列的代表已被证明是有效的长效口服活性LTB4受体抑制剂。
A series of carboxy-substituted cinnamides were investigated as antagonists of the human cell surface leukotriene B-4 (LTB4) receptor. Binding was determined through measurement of [H-3]-LTB4 displacement from human neutrophils. Receptor antagonism was confirmed through a functional assay, which measures inhibition of Ca2+ release in human neutrophils. Potent antagonists were discovered through optimization of a random screening hit, a p-(alpha-methylbenzyloxy)cinnamide, having low-micromolar activity. Substantial improvement of in vitro potency was realized by the attachment of a carboxylic acid moiety to the cinnamide phenyl ring through a flexible tether, leading to identification of compounds with low-nanomolar potency. Modification of the benzyloxy substituent, either through ortho-substitution on the benzyloxy phenyl group or through replacement of the ether oxygen with a methylene or sulfur atom, produced achiral antagonists of equal or greater potency. The most potent compounds in vitro were assayed for oral activity using the arachidonic acid-induced mouse ear edema model of inflammation. Several compounds in this series were found to significantly inhibit edema formation and myeloperoxidase activity in this model up to 17 h after oral administration. Representatives of this series have been shown to be potent and long-acting orally active inhibitors of the LTB4 receptor.