Developing Locally Bioavailable Drugs to Inhibit the Aberrantly Elevated PEG2 in the Colon - Abstract:
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.