AI Article Synopsis
- Human African trypanosomiasis causes thousands of deaths annually in rural Africa, highlighting the need for new treatments.
- Researchers focused on phtalazinone derivatives targeting phosphodiesterases as a potential therapy for neglected parasitic diseases.
- Although initial compounds showed promise as inhibitors, modifications led to a derivative with improved stability, making it a viable candidate for further development.
Article 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 resulted in being a potent TbrPDEB1 inhibitor with interesting activity against in a phenotypic screen. Derivative was studied in an acute 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 . Compound presented a good microsomal stability in mouse and human microsomes and provides a good starting point for future efforts.
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| http://dx.doi.org/10.1021/acs.jmedchem.9b00985 | DOI Listing |
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