Synthesis and biological evaluation of C(5)-substituted derivatives of leukotriene biosynthesis inhibitor BRP-7

Levent S., Gerstmeier J., OLĞAÇ A. , Nikels F., Garscha U., Carotti A., ...More

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol.122, pp.510-519, 2016 (Journal Indexed in SCI) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 122
  • Publication Date: 2016
  • Doi Number: 10.1016/j.ejmech.2016.07.004
  • Page Numbers: pp.510-519


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.