期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 122, 期 -, 页码 510-519出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2016.07.004
关键词
Leukotriene; 5-Lipoxygenase-activating protein; FLAP; Benzimidazole; BRP-7
资金
- Scientific and Technological Research Council of Turkey (TUBITAK) [112S596]
Pharmacological intervention with 5-lipoxygenase (5-LO) pathway leading to suppression of leukotriene (LT) biosynthesis is a clinically validated strategy for treatment of respiratory and cardiovascular diseases such as asthma and atherosclerosis. Here we describe the synthesis of a series of C(5)-substituted analogues of the previously described 5-LO-activating protein (FLAP) inhibitor BRP-7 (IC50 = 031 mu M) to explore the effects of substitution at the C(5)-benzimidazole (BI) ring as a strategy to increase the potency against FLAP-mediated 5-LO product formation. Incorporation of polar substituents on the C(5) position of the BI core, exemplified by compound 11 with a C(5)-nitrile substituent, significantly enhances the potency for suppression of 5-LO product synthesis in human neutrophils (IC50 = 0.07 mu M) and monocytes (IC50 = 0.026 mu M). (C) 2016 Elsevier Masson SAS. All rights reserved.
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