Salado, Irene G., Singh, Abhimanyu K., Moreno-Cinos, Carlos, Sakaine, Guna, Siderius, Marco, Van der Veken, Pieter, Matheeussen, An, van der Meer, Tiffany, Sadek, Payman, Gul, Sheraz, and others. (2020) Lead Optimization of Phthalazinone Phosphodiesterase Inhibitors as Novel Antitrypanosomal Compounds. Journal of Medicinal Chemistry, . ISSN 0022-2623. (doi:10.1021/acs.jmedchem.9b00985) (KAR id:80697)
|
PDF
Author's Accepted Manuscript
Language: English |
|
|
Download (433kB)
Preview
|
Preview |
|
This file may not be suitable for users of assistive technology.
Request an accessible format
|
|
| Official URL: https://doi.org/10.1021/acs.jmedchem.9b00985 |
|
Abstract
Human African trypanosomiasis is causing thousands of deaths every year in the rural areas of Africa. In this manuscript we describe the optimization of a family of phtalazinone derivatives. Phosphodiesterases have emerged as attractive molecular targets for a novel treatment for a variety of neglected parasitic diseases. Compound 1 resulted in being a potent TbrPDEB1 inhibitor with interesting activity against T. brucei in a phenotypic screen. Derivative 1 was studied in an acute in vivo mouse disease model but unfortunately showed no efficacy due to low metabolic stability. We report structural modifications to achieve compounds with an improved metabolic stability while maintaining high potency against TbrPDEB1 and T. brucei. Compound 14 presented a good microsomal stability in mouse and human microsomes and provides a good starting point for future efforts.
| Item Type: | Article |
|---|---|
| DOI/Identification number: | 10.1021/acs.jmedchem.9b00985 |
| Subjects: | Q Science |
| Divisions: | Divisions > Division of Natural Sciences > Biosciences |
| Depositing User: | David Brown |
| Date Deposited: | 02 Apr 2020 09:57 UTC |
| Last Modified: | 19 Mar 2021 00:00 UTC |
| Resource URI: | https://kar.kent.ac.uk/id/eprint/80697 (The current URI for this page, for reference purposes) |
| Brown, David: |  https://orcid.org/0000-0003-4605-4779 |
- Link to SensusAccess
- Export to:
- RefWorks
- EPrints3 XML
- BibTeX
- CSV
- Depositors only (login required):
Altmetric
Altmetric
