Levent Serkan, Gerstmeier Jana, Olgaç Abdurrahman, Nikels Felix, Garscha Ulrike, Carotti Andrea, Macchiarulo Antonio, Werz Oliver, Banoglu Erden, Çalışkan Burcu
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Yenimahalle, 06330 Ankara, Turkey.
Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, Philosophenweg 14, D-07743 Jena, Germany.
Eur J Med Chem. 2016 Oct 21;122:510-519. doi: 10.1016/j.ejmech.2016.07.004. Epub 2016 Jul 5.
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 = 0.31 μM) 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 μM) and monocytes (IC50 = 0.026 μM).
通过5-脂氧合酶（5-LO）途径进行药理干预以抑制白三烯（LT）生物合成，是治疗哮喘和动脉粥样硬化等呼吸和心血管疾病的一种经过临床验证的策略。在此，我们描述了一系列先前所述的5-LO激活蛋白（FLAP）抑制剂BRP-7（IC50 = 0.31 μM）的C（5）-取代类似物的合成，以探索在C（5）-苯并咪唑（BI）环上进行取代的效果，作为提高针对FLAP介导的5-LO产物形成的效力的一种策略。在BI核心的C（5）位置引入极性取代基，以具有C（5）-腈取代基的化合物11为例，可显著提高抑制人中性粒细胞（IC50 = 0.07 μM）和单核细胞（IC50 = 0.026 μM）中5-LO产物合成的效力。
