Hepatic encephalopathy is a neuropsychiatric complication of liver disease which is partly associated with elevated ammonemia. Urea hydrolysis by urease-producing bacteria in the colon is often mentioned as one of the main routes of ammonia production in the body, yet research on treatments targeting bacterial ureases in hepatic encephalopathy is limited. Herein we report a hydroxamate-based urease inhibitor, 2-octynohydroxamic acid, exhibiting improved in vitro potency compared to hydroxamic acids that were previously investigated for hepatic encephalopathy. 2-octynohydroxamic acid shows low cytotoxic and mutagenic potential within a micromolar concentration range as well as reduces ammonemia in rodent models of liver disease. Furthermore, 2-octynohydroxamic acid treatment decreases cerebellar glutamine, a product of ammonia metabolism, in male bile duct ligated rats. A prototype colonic formulation enables reduced systemic exposure to 2-octynohydroxamic acid in male dogs. Overall, this work suggests that urease inhibitors delivered to the colon by means of colonic formulations represent a prospective approach for the treatment of hepatic encephalopathy.

肝性脑病是肝病的一种神经精神并发症，部分与氨血症升高有关。结肠中产生脲酶的细菌对尿素的水解通常被认为是体内产生氨的主要途径之一，但针对肝性脑病中细菌脲酶的治疗研究却很有限。在此，我们报道了一种基于异羟肟酸的脲酶抑制剂，2-辛炔异羟肟酸，与之前研究的肝性脑病异羟肟酸相比，其体外效力有所改善。 2-辛炔异羟肟酸在微摩尔浓度范围内显示出低细胞毒性和致突变性，并可降低啮齿动物肝病模型中的氨血症。此外，2-辛炔异羟肟酸治疗可降低雄性胆管结扎大鼠的小脑谷氨酰胺（氨代谢的产物）。原型结肠制剂能够减少雄性犬体内 2-辛炔异羟肟酸的全身暴露。总体而言，这项工作表明，通过结肠制剂将脲酶抑制剂递送至结肠代表了治疗肝性脑病的一种前瞻性方法。