Development of the orally delivered, non-absorbable ACE inhibitor enalaprilat for

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): A major limitation with most current medical therapies for inflammatory bowel disease (IBD) is the indiscriminant immunosuppressive effect of these drugs. We have recently demonstrated the ability to palliate the progression of colitis in a mouse dextran sodium sulfate (DSS) model through blockage of signaling via the inhibition of the angiotensin-converting enzyme (ACE) in the renin-angiotensin system. The intervention leads to significant reduction in the clinical severity of colitis, improvement in histologic scores and a down-regulation in the expression of pro-inflammatory cytokines. The ACE enzyme catalyzes the conversion of angiotensin I to angiotensin II, which in turn triggers the NF:B cascade, ultimately resulting in apoptosis. Angiotensin II is also involved in the initiation of fibrosis formation. Hence, pursuing potent inhibitors of ACE, such as enalaprilat, has the potential to result in a potent and selective therapy for IBD. Although this treatment shows tremendous potential in treating IBD, a major consequence of the ACE inhibition is systemic hypotension seen with most currently marketed oral ACE inhibitors. Enalaprilat, however, is marketed as an intravenous formulation, since it shows poor oral absorption, a characteristic that is highly desirable for the local treatment of IBD. Preliminary pre-clinical studies with enalaprilat demonstrate very high efficacy in the treatment of colitis when delivered via the trans-anal route, without systemic hemodynamic side-effects. Due to its poor oral availability and strong potency against ACE, we hypothesize that enalaprilat is an ideal candidate for oral delivery. We propose to characterize enalaprilat's absorption potential along the entire gastrointestinal tract in diseased and healthy mice to determine if simple oral tablet dosing could be a feasible delivery strategy for enalaprilat for both ulcerative colitis as well as Crohn's disease. Finally, we will determine the efficacy of enalaprilat in preclinical murine models of IBD. The goal of this proposal is to develop an entirely new type of drug therapy for IBD using an existing, proven safe therapeutic, and focusing on local control of the inflammatory response, without systemic side effects. Since this class of drugs is not currently used for IBD, this approach potentially could be used as either a single therapy, or added to current regimens, allowing for reduced systemic immune suppression. Findings from these studies could lead to a unique strategy to treat inflammatory bowel disease. TSRL has formed collaboration with Dr. Dan Teitelbaum of the University of Michigan to address this problem. The team brings a wealth of experience and expertise in the areas of inflammatory bowel disease pharmacology and oral absorption strategies to the program. PUBLIC HEALTH RELEVANCE: This phase I SBIR project is seeking to develop an existing antihypertensive medicine for an additional indication, the treatment of inflammatory bowel disease. Inflammatory bowel disease is a debilitating disease that is currently only treatable with drugs which cause significant side effects. The goal is the development of a medicine with proven safety that can be easily taken by mouth both during a flare-up of the disease as well as a maintenance treatment.