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

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2023 Jul 20

PMID 37471520

Authors

Yang Zheng

Magali van den Kerkhof

Tiffany van der Meer

Sheraz Gul

Maria Kuzikov

Bernhard Ellinger

Iwan J P de Esch

Marco Siderius

An Matheeussen

Louis Maes

Geert Jan Sterk

Guy Caljon

Rob Leurs

Affiliations

Soon will be listed here.

Abstract

Human African Trypanosomiasis (HAT), caused by , 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, (NPD-2975), has an in vitro IC of 70 nM against with no apparent toxicity against human MRC-5 lung fibroblasts. Showing good physicochemical properties, low toxicity potential, acceptable metabolic stability, and other pharmacokinetic features, was further evaluated in an acute mouse model of 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 represents a promising lead for future drug development to treat HAT.

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Lead Optimization of the 5-Phenylpyrazolopyrimidinone NPD-2975 toward Compounds with Improved Antitrypanosomal Efficacy.

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