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Developing Locally Bioavailable Drugs to Inhibit the Aberrantly Elevated PEG2 in the Colon

Award Number: R15GM126475
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2018
PERIOD OF PERFORMANCE END DATE: 02/28/2022

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = -$42,879 )
2023	2018	TEXAS SOUTHERN UNIVERSITY	3100 CLEBURNE ST	HOUSTON	TX	77004	HARRIS	USA	Biomedical Research and Research Training	000	1	12/9/2022	NEW	-$42,879
														Subtotal = -$42,879

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2018	TEXAS SOUTHERN UNIVERSITY	3100 CLEBURNE ST	HOUSTON	TX	77004	HARRIS	USA	Biomedical Research and Research Training	000	1	3/7/2022	NEW	-$147,207
2022	2018	TEXAS SOUTHERN UNIVERSITY	3100 CLEBURNE ST	HOUSTON	TX	77004	HARRIS	USA	Biomedical Research and Research Training	001	1	6/29/2022	NEW	$147,207
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2018	TEXAS SOUTHERN UNIVERSITY	3100 CLEBURNE ST	HOUSTON	TX	77004	HARRIS	USA	Biomedical Research and Research Training	000	1	2/8/2019	NEW	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $472,250 )
2018	2018	TEXAS SOUTHERN UNIVERSITY	3100 CLEBURNE ST	HOUSTON	TX	77004	HARRIS	USA	Biomedical Research and Research Training	000	1	9/13/2018	NEW	$472,250
														Subtotal = $472,250

Grand Total All Awards = $429,371

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Developing Locally Bioavailable Drugs to Inhibit the Aberrantly Elevated PEG2 in the Colon

Award Number: R15GM126475

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/15/2018

PERIOD OF PERFORMANCE END DATE: 02/28/2022

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