Published January 1, 2016
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Synthesis and biological evaluation of C(5)-substituted derivatives of leukotriene biosynthesis inhibitor BRP-7
Creators
- 1. Gazi Univ, Fac Pharm, Dept Pharmaceut Chem, TR-06330 Ankara, Turkey
- 2. Univ Jena, Inst Pharm, Chair Pharmaceut Med Chem, Philosophenweg 14, D-07743 Jena, Germany
- 3. Univ Perugia, Dipartimento Sci Farmaceut, Via Liceo 1, I-06123 Perugia, Italy
Description
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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