Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Ankara, Turkey.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Ankara, Turkey.
Eur J Med Chem. 2018 Jun 10;153:34-48. doi: 10.1016/j.ejmech.2017.07.019. Epub 2017 Jul 13.
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.
白三烯是与多种慢性炎症性疾病相关的促炎脂质介质，如哮喘、COPD、IBD、关节炎、动脉粥样硬化、皮炎和癌症。细胞白三烯是由花生四烯酸通过 5-脂氧合酶途径产生的，其中 5-脂氧合酶激活蛋白（也称为 FLAP）通过作为将花生四烯酸有效转移到 5-脂氧合酶的调节蛋白发挥关键作用。通过阻断白三烯的产生，FLAP 抑制剂可能作为广谱白三烯调节剂发挥作用，这可能对需要抗白三烯治疗的慢性炎症性疾病具有治疗作用。FLAP 抑制剂（即 MK-886、MK-591、BAY-X-1005）的早期开发主要集中在哮喘治疗上，并在哮喘患者的临床前和临床研究中产生了有希望的结果。在最近阐明了 FLAP 的 3D 结构之后，新的抑制剂化学型的开发得到了极大的加速，最终导致许多非药物样结构演变成更具药物样特征的实体，如 AZD6642 和 BI665915 作为开发候选物。迄今为止，最具临床开发前景的 FLAP 抑制剂是 GSK2190918（以前称为 AM803），它已成功完成哮喘患者的 II 期临床试验。总之，尽管目前还没有 FLAP 抑制剂进入药物批准阶段，但由于抗 LT 治疗的适应症数量不断增加，如动脉粥样硬化，FLAP 抑制剂的开发仍然是一个重要的研究领域。本文综述的 FLAP 抑制剂分为四类：第一代 FLAP 抑制剂（吲哚和喹啉衍生物）、第二代 FLAP 抑制剂（二芳基-烷烃和二芳基氨基杂芳烃）、含苯并咪唑的 FLAP 抑制剂和其他具有多药理学的 FLAP 抑制剂，以便于读者理解。因此，我们详细总结了 FLAP 抑制剂是如何从无到有发展到目前的先进状态的，并让读者对 FLAP 抑制剂可能很快满足需要抗 LT 治疗的患者的需求持积极态度。
