Amira Pharmaceuticals, San Diego, California, USA.
Clin Pharmacol Ther. 2010 Apr;87(4):437-44. doi: 10.1038/clpt.2009.301. Epub 2010 Feb 24.
The 5-lipoxygenase-activating protein (FLAP) gene and an increase in leukotriene (LT) production are linked to the risk of asthma, myocardial infarction, and stroke. We evaluated the pharmacodynamics, pharmacokinetics, and tolerability of 3-[3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (AM103), a novel FLAP inhibitor, in healthy subjects. Single and multiple doses of AM103 demonstrated dose-dependent inhibition of blood LTB(4) production and dose-related inhibition of urinary LTE(4). After a single oral dose (50-1,000 mg) of AM103, the maximum concentration (C(max)) and area under the curve (AUC) in plasma increased in a dose-dependent manner. After multiple-dose administration (50-1,000 mg once daily for 11 days), there were no significant differences in the pharmacokinetic parameters between the first and last days of treatment. AM103 was well tolerated at all doses in both the single- and multiple-dose cohorts. Further clinical trials with AM103 in inflammatory diseases are warranted.
5-脂氧合酶激活蛋白（FLAP）基因和白三烯（LT）产量的增加与哮喘、心肌梗死和中风的风险有关。我们评估了新型 FLAP 抑制剂 3-[3-叔丁基硫基-1-[4-（6-甲氧基-吡啶-3-基）-苄基]-5-（吡啶-2-基甲氧基）-1H-吲哚-2-基]-2,2-二甲基-丙酸（AM103）在健康受试者中的药效学、药代动力学和耐受性。AM103 的单剂量和多剂量研究表明，其可剂量依赖性抑制血液 LTB4 的产生，并呈剂量相关性抑制尿 LTE4。在单次口服 AM103（50-1,000 mg）后，C(max)和 AUC 在血浆中呈剂量依赖性增加。在多剂量给药（50-1,000 mg 每日一次，共 11 天）后，治疗的第 1 天和最后 1 天之间，药代动力学参数没有显著差异。在单剂量和多剂量队列中，AM103 在所有剂量下均具有良好的耐受性。需要进一步的临床试验来评估 AM103 在炎症性疾病中的应用。
