Lead Optimization of Phthalazinone Phosphodiesterase Inhibitors as Novel Antitrypanosomal Compounds

Irene G. Salado, Abhimanyu K. Singh, Carlos Moreno-Cinos, Guna Sakaine, Marco Siderius, Pieter Van der Veken, An Matheeussen, Tiffany van der Meer, Payman Sadek, Sheraz Gul, Louis Maes, Geert Jan Sterk, Rob Leurs, David Brown, Koen Augustyns

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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.

Original languageEnglish
Pages (from-to)3485-3507
Number of pages23
JournalJournal of medicinal chemistry
Volume63
Issue number7
Early online date20 Mar 2020
DOIs
Publication statusPublished - 9 Apr 2020

Funding

This research was funded by European Commission 7th Framework Programme FP7 HEALTH-2013-INNOVATION-1 under Project Reference 602666 “Parasite-Specific Cyclic Nucleotide Phosphodiesterase Inhibitors to Target Neglected Parasitic Diseases” (Grant PDE4NPD). We thank staff of Diamond Light Source beamlines I03 and I04 (Didcot, U.K.) for their help in X-ray diffraction data collection. G.S. thanks the EC 7th Framework Programme Project REGPOT-CT-2013-316149-InnovaBalt. To develop new molecules able to cure this disease, a public–private consortium has been established funded by the European Union. This project, named “Parasite-Specific Cyclic Nucleotide Phosphodiesterase Inhibitors To Target Neglected Parasitic Diseases”, has validated parasitic cyclic nucleotide phosphodiesterases as valuable targets for drug discovery and has identified parasite-specific features of the PDE active sites.

FundersFunder number
European Commission 7th Framework Programme FP7 HEALTH-2013-INNOVATION-1PDE4NPD
Seventh Framework Programme602666
European Commission

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