A new treatment for NSAID-associated gastrointestinal damage

 描述(申请人提供)：非类固醇抗炎药(NSAIDs)是最广泛使用的药物之一，但它们的长期使用会导致胃部损伤和小肠损伤。以往的研究表明，Anandamide是一种产生于胃肠道(GI)粘膜的内源性内源性大麻素类物质，在上皮的动态平衡和修复中发挥着重要作用。花生胺的生物学作用是由细胞内的脂肪酸酰胺水解酶(FAAH)终止的。为了探索阿南达胺在外周组织中的作用，我们最近开发了一类新的小分子FAAH抑制剂，它只在身体外周抑制阿南达胺的失活。以前的选择性、安全性和药代动力学研究已经确定了这一类的原型成员，一种名为URB937的化合物，是临床前开发的潜在候选药物。我们最近发现，URB937通过放大内源性产生的ANANDAME介导的保护性反馈机制，抑制NSAID诱导的动物模型的胃损伤。这些结果表明，URB937可能提供一种变革性的方法来预防和/或治疗与长期使用非甾体抗炎药相关的胃和肠道损害。我们的建议有两个主要目标：(1)确定URB937在急性NSAID诱导的胃损伤模型中的比较疗效。我们将研究不同剂量的URB937口服的效果，并与目前临床上使用的两种胃保护药物(奥美拉唑和米索前列醇)进行比较，在急性非类固醇抗炎药引起的胃病的标准临床前模型中(使用有效的非甾体抗炎药消炎痛)。(2)确定URB937对慢性非甾体抗炎药所致胃肠损伤的预防作用。我们将研究URB937能否(I)预防慢性消炎痛引起的胃病和肠病；以及(Ii)预防慢性阿司匹林引起的胃病。这些模型模拟了URB937的胃肠道保护作用可能在临床上应用的两个不同环境：继续接受非类固醇抗炎药治疗的患者与非类固醇抗炎药相关的胃肠道损伤的愈合，以及服用低剂量阿司匹林的心血管患者的消化性溃疡的预防。如果该化合物满足以下至少一项标准，URB937的开发将继续进行：(I)在预防急性和慢性吲哚美辛造成的胃肠道损伤方面的活动，或(Ii)在防止慢性阿司匹林造成的胃损伤方面的活动。如果符合这两个标准中的一个或两个，我们将申请STTR第二阶段资金，将URB937转移到非类固醇胃肠病的全面临床前开发。

 DESCRIPTION (provided by applicant): Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely consumed pharmaceuticals, but their prolonged use causes gastric injury and damage to the small intestine. Previous work has shown that anandamide, an endogenous endocannabinoid substance produced in the gastrointestinal (GI) mucosa, plays an important role in epithelial homeostasis and repair. The biological actions of anandamide are terminated by the intracellular enzyme, fatty acid amide hydrolase (FAAH). To explore the role of anandamide in peripheral tissues, we have recently developed a novel class of small-molecule FAAH inhibitors that suppress anandamide deactivation only in the periphery of the body. Previous selectivity, safety and pharmacokinetic studies have identified the prototype member of this class, a compound called URB937, as a potential lead candidate for preclinical development. We recently discovered that URB937 suppresses NSAID-induced gastric damage in animal models by amplifying a protective feedback mechanism mediated by endogenously produced anandamide. These results suggest that URB937 might offer a transformative approach to prevent and/or treat gastric and intestinal damage associated with prolonged NSAID use. Our proposal has two primary goals: (1) Determine the comparative efficacy of URB937 in a model of acute NSAID-induced gastric damage. We will investigate the effects of different oral dosages of URB937, and compare them to those of two gastroprotectant drugs currently employed in the clinic (omeprazole and misoprostol), in a standard preclinical model of acute NSAID-induced gastropathy (using the potent NSAID, indomethacin). (2) Determine the efficacy of URB937 in the prevention of chronic NSAID-induced gastric and intestinal damage. We will examine whether URB937 can (i) prevent the gastropathy and enteropathy elicited by chronic indomethacin; and (ii) prevent the gastropathy produced by chronic aspirin. These models mimic two distinct settings where the GI-protecting effects of URB937 might find clinical application: healing of NSAID-associated GI damage in patients continuing NSAID therapy, and prevention of peptic ulcers in cardiovascular patients taking low-dose aspirin. Development of URB937 will be continued if the compound fulfills at least one of the following criteria (i) activiy in preventing GI damage produced by acute and chronic indomethacin, or (ii) activity in preventing gastric damage produced by chronic aspirin. If either or both of these criteria is met, we will apply for STTR Phase 2 funding to move URB937 to full preclinical development for NSAID gastroenteropathy.