2. Academic Validation
  3. Discovery of 5-Phenylpyrazolopyrimidinone Analogs as Potent Antitrypanosomal Agents with In Vivo Efficacy

Discovery of 5-Phenylpyrazolopyrimidinone Analogs as Potent Antitrypanosomal Agents with In Vivo Efficacy

  • J Med Chem. 2023 Aug 10;66(15):10252-10264. doi: 10.1021/acs.jmedchem.3c00161.
Yang Zheng 1,  Magali van den Kerkhof 2,  Tiffany van der Meer 1,  Sheraz Gul 3 4,  Maria Kuzikov 3 4,  Bernhard Ellinger 3 4,  Iwan J P de Esch 1,  Marco Siderius 1,  An Matheeussen 2,  Louis Maes 2,  Geert Jan Sterk 1,  Guy Caljon 2,  Rob Leurs 1
Affiliations

Affiliations

  • 1 Amsterdam Institute for Molecules, Medicines and Systems, Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.
  • 2 Laboratory of Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium.
  • 3 Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, 22525 Hamburg, Germany.
  • 4 Fraunhofer Cluster of Excellence for Immune-Mediated Diseases CIMD, 22525 Hamburg, Germany.
PMID: 37471520 DOI: 10.1021/acs.jmedchem.3c00161
Abstract

Human African Trypanosomiasis (HAT), caused by Trypanosoma brucei, is one of the neglected tropical diseases with a continuing need for new medication. We here describe the discovery of 5-phenylpyrazolopyrimidinone analogs as a novel series of phenotypic antitrypanosomal agents. The most potent compound, 30 (NPD-2975), has an in vitro IC50 of 70 nM against T. b. brucei with no apparent toxicity against human MRC-5 lung fibroblasts. Showing good physicochemical properties, low toxicity potential, acceptable metabolic stability, and other pharmacokinetic features, 30 was further evaluated in an acute mouse model of T. b. brucei Infection. After oral dosing at 50 mg/kg twice per day for five consecutive days, all infected mice were cured. Given its good drug-like properties and high in vivo antitrypanosomal potential, the 5-phenylpyrazolopyrimidinone analog 30 represents a promising lead for future drug development to treat HAT.

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