Sundermann Tom, Hanekamp Walburga, Lehr Matthias
a Department of Chemistry and Pharmacy , Institute of Pharmaceutical and Medicinal Chemistry, University of Münster , Münster , Germany.
J Enzyme Inhib Med Chem. 2016 Aug;31(4):653-63. doi: 10.3109/14756366.2015.1057721. Epub 2015 Jul 7.
Cytosolic phospholipase A2α (cPLA2α) and fatty acid amide hydrolase (FAAH) are serine hydrolases. cPLA2α is involved in the generation of pro-inflammatory lipid mediators, FAAH terminates the anti-inflammatory effects of endocannabinoids. Therefore, inhibitors of these enzymes may represent new drug candidates for the treatment of inflammation. We have reported that certain 1-heteroarylpropan-2-ones are potent inhibitors of cPLA2α and FAAH. The serine reactive ketone group of these compounds, which is crucial for enzyme inhibition, is readily metabolized resulting in inactive alcohol derivatives. In order to obtain metabolically more stable inhibitors, we replaced this moiety by α-ketoheterocyle, cyanamide and nitrile serine traps. Investigations on activity and metabolic stability of these substances revealed that in all cases an increased metabolic stability was accompanied by a loss of inhibitory potency against cPLA2α and FAAH, respectively.
胞质型磷脂酶A2α（cPLA2α）和脂肪酸酰胺水解酶（FAAH）属于丝氨酸水解酶。cPLA2α参与促炎脂质介质的生成，FAAH则终止内源性大麻素的抗炎作用。因此，这些酶的抑制剂可能成为治疗炎症的新型候选药物。我们曾报道某些1-杂芳基丙烷-2-酮是cPLA2α和FAAH的强效抑制剂。这些化合物的丝氨酸反应性酮基对酶抑制作用至关重要，但极易被代谢，生成无活性的醇衍生物。为了获得代谢稳定性更高的抑制剂，我们用α-酮杂环、氰胺和腈丝氨酸捕获剂取代了该基团。对这些物质的活性和代谢稳定性进行研究后发现，在所有情况下，代谢稳定性的提高都分别伴随着对cPLA2α和FAAH抑制效力的丧失。
