Drug discovery approaches targeting 5-lipoxygenase-activating protein (FLAP) for inhibition of cellular leukotriene biosynthesis

白三烯 化学 花生四烯酸5-脂氧合酶 药理学 生物化学 促炎细胞因子 药品 药物开发 花生四烯酸 哮喘 炎症 免疫学 医学
作者
Tuğçe Gür Maz,Burcu Çalışkan,Erden Banoğlu
出处
期刊:European journal of medicinal chemistry [Elsevier BV]
卷期号:153: 34-48 被引量:60
标识
DOI:10.1016/j.ejmech.2017.07.019
摘要

Leukotrienes are proinflammatory lipid mediators associated with diverse chronic inflammatory diseases such as asthma, COPD, IBD, arthritis, atherosclerosis, dermatitis and cancer. Cellular leukotrienes are produced from arachidonic acid via the 5-lipoxygenase pathway in which the 5-lipoxygenase activating protein, also named as FLAP, plays a critical role by operating as a regulatory protein for efficient transfer of arachidonic acid to 5-lipoxygenase. By blocking leukotriene production, FLAP inhibitors may behave as broad-spectrum leukotriene modulators, which might be of therapeutic use for chronic inflammatory diseases requiring anti-leukotriene therapy. The early development of FLAP inhibitors (i.e. MK-886, MK-591, BAY-X-1005) mostly concentrated on asthma cure, and resulted in promising readouts in preclinical and clinical studies with asthma patients. Following the recent elucidation of the 3D-structure of FLAP, development of new inhibitor chemotypes is highly accelerated, eventually leading to the evolution of many un-drug-like structures into more drug-like entities such as AZD6642 and BI665915 as development candidates. The most clinically advanced FLAP inhibitor to date is GSK2190918 (formerly AM803) that has successfully completed phase II clinical trials in asthmatics. Concluding, although there are no FLAP inhibitors reached to the drug approval phase yet, due to the rising number of indications for anti-LT therapy such as atherosclerosis, FLAP inhibitor development remains a significant research field. FLAP inhibitors reviewed herein are classified into four sub-classes as the first-generation FLAP inhibitors (indole and quinoline derivatives), the second-generation FLAP inhibitors (diaryl-alkanes and biaryl amino-heteroarenes), the benzimidazole-containing FLAP inhibitors and other FLAP inhibitors with polypharmacology for easiness of the reader. Hence, we meticulously summarize how FLAP inhibitors historically developed from scratch to their current advanced state, and leave the reader with a positive view that a FLAP inhibitor might soon reach to the need of patients who may require anti-LT therapy.
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