J Med Chem. 2019 May 9;62(9):4325-4349. doi: 10.1021/acs.jmedchem.8b02012. Epub 2019 Apr 15.
5-Lipoxygenase (5-LO)-activating protein (FLAP) inhibitors have proven to attenuate 5-LO pathway activity and leukotriene production in human clinical trials. However, previous clinical candidates have been discontinued and the link between FLAP inhibition and outcome in inflammatory diseases remains to be established. We here describe a novel series of FLAP inhibitors identified from a screen of 10k compounds and the medicinal chemistry strategies undertaken to progress this series. Compound 4i showed good overall properties and a pIC hWB of 8.1 and an lipophilic ligand efficiency of 5.2. Target engagement for 4i was established in dogs using ex vivo measurement of leukotriene B (LTB) levels in blood with good correlation to in vitro potency. A predicted human dose of 280 mg b.i.d. suggests a wide margin to any identified in vitro off-target effects and sufficient exposure to achieve an 80% reduction of LTB levels in humans. Compound 4i is progressed to preclinical in vivo safety studies.
5-脂氧合酶 (5-LO)-激活蛋白 (FLAP) 抑制剂已被证明可在人体临床试验中减弱 5-LO 途径的活性和白三烯的产生。然而，先前的临床候选药物已被停用，FLAP 抑制与炎症性疾病的结果之间的联系仍有待确定。我们在这里描述了从 10k 化合物筛选中鉴定出的一系列新型 FLAP 抑制剂，以及为推进该系列所采取的药物化学策略。化合物 4i 表现出良好的整体性质，hWB pIC 为 8.1，亲脂性配体效率为 5.2。使用在体血液中白三烯 B（LTB）水平的离体测量，在狗中建立了化合物 4i 的靶标结合，与体外效力具有良好的相关性。预测的人类剂量为 280mg b.i.d. 表明与任何已确定的体外脱靶效应有很大的差距，并且有足够的暴露量可使人类的 LTB 水平降低 80%。化合物 4i 正在推进临床前体内安全性研究。
