Long, Keith
(2022)
MEDICINAL CHEMISTRY APPROACHES TO ACUTE KIDNEY INJURY.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Acute kidney injury (AKI) is a serious condition that negatively contributes to the morbidity and mortality of hospitalized patients. Unfortunately, despite the tremendous need, no specific treatment exists to treat AKI, and there are no clinically validated therapeutic targets. The work described contributes to closing this gap by developing tools to improve interpretation of data in zebrafish assays, to validate a target for AKI using phenotypic screens in zebrafish, to identify drug discovery starting points, and to rationally optimize those starting points. In interpreting results from embryonic zebrafish assays, negative results can be due to no specific biological activity and/or the compound not accessing its target. Using a collection of compounds that are biologically active in zebrafish, a set of predicted chemical property parameters was developed that can improve SAR data interpretation. To validate a therapeutic target for AKI, we evaluated multiple selective inhibitors of HDAC 8 from varied scaffolds in a series of increasingly stringent AKI assays. PCI-34051 was particularly effective in multiple models thus validating HDAC 8 as a target for AKI and providing a starting point for AKI drug discovery. Lead optimization on PCI-34051 focused on the hydroxamic acid zinc binding group (ZBG). Novel analogs to PCI-34051 were designed using known ZBG from the literature, synthesized, and tested. The approaches outlined in this work provide foundational knowledge for the discovery of a small molecule therapy for AKI.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
6 December 2022 |
| Date Type: |
Publication |
| Defense Date: |
4 November 2022 |
| Approval Date: |
6 December 2022 |
| Submission Date: |
5 December 2022 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
234 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Pharmacy > Pharmaceutical Sciences |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Medicinal Chemistry
Acute Kidney Injury
Zebrafish
Histone Deacetylase
Bioisostere
Rational Drug Design |
| Date Deposited: |
06 Dec 2022 16:55 |
| Last Modified: |
06 Dec 2023 06:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/43935 |
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