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., ...Daha Fazla

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, cilt.122, ss.510-519, 2016 (SCI İndekslerine Giren Dergi) identifier identifier identifier

  • Cilt numarası: 122
  • Basım Tarihi: 2016
  • Doi Numarası: 10.1016/j.ejmech.2016.07.004
  • Dergi Adı: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
  • Sayfa Sayıları: ss.510-519

Özet

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.