化学
吲哚试验
酮
磷脂酶A2
花生四烯酸
酶
立体化学
羧酸
胞浆
生物化学
流出
有机化学
作者
Angelina Subeska,Merlin Ekodo Voundi,Walburga Hanekamp,Dennis Mulac,Klaus Langer,Matthias Lehr
标识
DOI:10.1016/j.bmcl.2023.129374
摘要
Cytosolic phospholipase A2 α (cPLA2 α), the key enzyme of the arachidonic acid cascade, is considered to be an interesting target for the development of new anti-inflammatory drugs. Potent inhibitors of the enzyme include indole-5-carboxylic acids with propan-2-one residues in position 1 of the indole. Previously, it was found that central pharmacophoric elements of these compounds are their ketone and carboxylic acid groups, which unfortunately are subject to pronounced metabolism by carbonyl reductases and glucuronosyl transferases, respectively. Here we show that the metabolic stability of these inhibitors can be improved by introducing alkyl substituents in the vicinity of the ketone group or by increasing their rigidity. Furthermore, permeability tests with Caco-2 cells revealed that the indole derivatives have only low permeability, which can be attributed to their affinity to efflux transporters. Among other things, the polar ketone group in the center of the molecules seems to be a decisive factor for their reverse transport. After its removal, the permeability increased significantly. The enhancement in metabolic stability and permeability achieved by the structural variations carried out was accompanied by a more or less pronounced decrease in the inhibitory potency of the compounds against cPLA2 α.
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