Physiological prostaglandin E2 (PGE2) is important for maintaining certain essential functions of the gastrointestinal (GI) tract (e.g., GI integrity and secretion). However, aberrantly elevated PGE2 (AbE-PGE2) production in the colon is strongly associated with several chronic diseases (e.g., colorectal cancer, chronic inflammation in the colon). Preclinical and clinical trials have shown that the suppression of AbE-PGE2 production can effectively prevent or treat these diseases, but developing drugs to specifically suppress colonic PGE2 using current drug development strategies is difficult because most drug development efforts aim to improve a drug?s systemic bioavailability, which usually leads to broad drug distribution into multiple organs at high concentration. This broad distribution can disrupt the homeostasis of prostanoids to cause severe side effects (e.g., unstable angina, myocardial infarction). In this application, we propose to develop locally bioavailable drugs (LBDs) to restrict the drug to the colon for the purpose of selectively suppressing local AbE-PGE2 production. We will use celecoxib, an PGE2 production inhibitor, as a reference compound to develop LBDs. Our hypothesis is that we can modify the structure of celecoxib to enable the derivatives to undergo enterohepatic recycling (EHR) in order to selectively inhibit AbE-PGE2 production in the colon without affecting systemic PGE2 or disrupting the homeostasis of prostanoids. In the preliminary study, we have already synthesized 13 celecoxib derivatives and identified two leading compounds (6a1 and 7a1) with desirable ADME profiles. In this application, we will synthesize additional celecoxib derivatives and determine their in vitro activities and ADME properties in order to advance our understanding of designing LBDs (Aim 1) and we will determine the in vivo PGE2 suppression activities of two potent LBD candidates and evaluate their impact on the systemic PGE2 level and the homeostasis of prostanoids (Aim 2). If successful this project will demonstrate that localization of a drug to the colon is achievable by targeting HER, and that LBDs are efficacious in suppressing local AbE-PGE2 in the colon without disturbing the homeostasis of systemic prostanoids. This project will allow us to generate preliminary data for the preparation of an R01-level proposal focusing on efficacy and toxicity studies of the LBD candidates and on extending the strategy to other LBD drugs. In addition, this innovative multidisciplinary project will allow us to train undergraduate students from various STEM disciplines and strengthen the research environment of our institution. We expect the research community to be able to use this novel approach to develop drugs for the treatment of other colonic diseases, especially those related to AbE-PGE2 production.
It is well-known that physiological level of Prostaglandin E2 (PGE2), a potent signaling molecule, is important to maintain some essential functions of gastrointestinal tract but aberrantly elevated PGE2 is strongly associated with several colonic diseases (e.g., colorectal cancer, chronic inflammation, etc.). However, it is challenge to develop drugs to selectively suppress the aberrantly elevated PGE2 in the colon because the homeostasis of systemic prostanoids is easily to be disrupted to cause severe side effects when a drug has high distribution systemically. In this application, we propose to develop a novel approach that can localize the drug only in the colon to achieve maximal local PGE2 suppression and minimal systemic disturbance. If the concept is successfully proven, novel drug candidates are expected to emerge for the treatment and/or prevention of the PGE2 related diseases in the colon with improved safety profiles.
