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

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

doi:10.1021/acs.jmedchem.3c00161

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

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^*

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	10252–10264
Number of pages	13
Journal	Journal of medicinal chemistry
Volume	66
Issue number	15
Early online date	20 Jul 2023
DOIs	https://doi.org/10.1021/acs.jmedchem.3c00161
Publication status	Published - 10 Aug 2023

Bibliographical note

Funding Information:
Lars Binkhorst, Odessa Visser, and Shresta Giasi are thanked for their synthetic assistance. Hans Custers, Andrea van de Stolpe, Pim-Bart Feijens, and Mathias Sempels are thanked for their technical assistance. Elwin Janssen is thanked for his NMR support. This work was supported by the European Commission 7 Framework Program FP7-HEALTH-2013-INNOVATION-1 under project reference 602666 “Parasite-specific cyclic nucleotide phosphodiesterase inhibitors to target Neglected Parasitic Diseases” (PDE4NPD). YZ acknowledges the China Scholarship Council (CSC) for funding (Grant no. 201506220185). LMPH is a partner of the Excellence Centre ‘Infla-Med’ ( www.uantwerpen.be/infla-med ) and participates in COST Action CA21111. th

Publisher Copyright:
© 2023 The Authors. Published by American Chemical Society.

Funding

Lars Binkhorst, Odessa Visser, and Shresta Giasi are thanked for their synthetic assistance. Hans Custers, Andrea van de Stolpe, Pim-Bart Feijens, and Mathias Sempels are thanked for their technical assistance. Elwin Janssen is thanked for his NMR support. This work was supported by the European Commission 7 Framework Program FP7-HEALTH-2013-INNOVATION-1 under project reference 602666 “Parasite-specific cyclic nucleotide phosphodiesterase inhibitors to target Neglected Parasitic Diseases” (PDE4NPD). YZ acknowledges the China Scholarship Council (CSC) for funding (Grant no. 201506220185). LMPH is a partner of the Excellence Centre ‘Infla-Med’ ( www.uantwerpen.be/infla-med ) and participates in COST Action CA21111. th

Funders	Funder number
European Commission 7 Framework Program FP7-HEALTH-2013-INNOVATION-1	PDE4NPD, 602666
European Commission 7th Framework Program FP7-HEALTH-2013-INNOVATION-1
European Cooperation in Science and Technology	CA21111
China Scholarship Council	201506220185

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Zheng, Y., van den Kerkhof, M., van der Meer, T., Gul, S., Kuzikov, M., Ellinger, B., de Esch, I. J. P., Siderius, M., Matheeussen, A., Maes, L., Sterk, G. J., Caljon, G., & Leurs, R. (2023). Discovery of 5-Phenylpyrazolopyrimidinone Analogs as Potent Antitrypanosomal Agents with In Vivo Efficacy. Journal of medicinal chemistry, 66(15), 10252–10264. https://doi.org/10.1021/acs.jmedchem.3c00161

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title = "Discovery of 5-Phenylpyrazolopyrimidinone Analogs as Potent Antitrypanosomal Agents with In Vivo Efficacy",

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.",

author = "Yang Zheng and {van den Kerkhof}, Magali and {van der Meer}, Tiffany and Sheraz Gul and Maria Kuzikov and Bernhard Ellinger and {de Esch}, {Iwan J.P.} and Marco Siderius and An Matheeussen and Louis Maes and Sterk, {Geert Jan} and Guy Caljon and Rob Leurs",

note = "Funding Information: Lars Binkhorst, Odessa Visser, and Shresta Giasi are thanked for their synthetic assistance. Hans Custers, Andrea van de Stolpe, Pim-Bart Feijens, and Mathias Sempels are thanked for their technical assistance. Elwin Janssen is thanked for his NMR support. This work was supported by the European Commission 7 Framework Program FP7-HEALTH-2013-INNOVATION-1 under project reference 602666 “Parasite-specific cyclic nucleotide phosphodiesterase inhibitors to target Neglected Parasitic Diseases” (PDE4NPD). YZ acknowledges the China Scholarship Council (CSC) for funding (Grant no. 201506220185). LMPH is a partner of the Excellence Centre {\textquoteleft}Infla-Med{\textquoteright} ( www.uantwerpen.be/infla-med ) and participates in COST Action CA21111. th Publisher Copyright: {\textcopyright} 2023 The Authors. Published by American Chemical Society.",

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Zheng, Y, van den Kerkhof, M, van der Meer, T, Gul, S, Kuzikov, M, Ellinger, B, de Esch, IJP , Siderius, M, Matheeussen, A, Maes, L, Sterk, GJ, Caljon, G & Leurs, R 2023, 'Discovery of 5-Phenylpyrazolopyrimidinone Analogs as Potent Antitrypanosomal Agents with In Vivo Efficacy', Journal of medicinal chemistry, vol. 66, no. 15, pp. 10252–10264. https://doi.org/10.1021/acs.jmedchem.3c00161

TY - JOUR

T1 - Discovery of 5-Phenylpyrazolopyrimidinone Analogs as Potent Antitrypanosomal Agents with In Vivo Efficacy

AU - Zheng, Yang

AU - van den Kerkhof, Magali

AU - van der Meer, Tiffany

AU - Gul, Sheraz

AU - Kuzikov, Maria

AU - Ellinger, Bernhard

AU - de Esch, Iwan J.P.

AU - Siderius, Marco

AU - Matheeussen, An

AU - Maes, Louis

AU - Sterk, Geert Jan

AU - Caljon, Guy

AU - Leurs, Rob

N1 - Funding Information: Lars Binkhorst, Odessa Visser, and Shresta Giasi are thanked for their synthetic assistance. Hans Custers, Andrea van de Stolpe, Pim-Bart Feijens, and Mathias Sempels are thanked for their technical assistance. Elwin Janssen is thanked for his NMR support. This work was supported by the European Commission 7 Framework Program FP7-HEALTH-2013-INNOVATION-1 under project reference 602666 “Parasite-specific cyclic nucleotide phosphodiesterase inhibitors to target Neglected Parasitic Diseases” (PDE4NPD). YZ acknowledges the China Scholarship Council (CSC) for funding (Grant no. 201506220185). LMPH is a partner of the Excellence Centre ‘Infla-Med’ ( www.uantwerpen.be/infla-med ) and participates in COST Action CA21111. th Publisher Copyright: © 2023 The Authors. Published by American Chemical Society.

PY - 2023/8/10

Y1 - 2023/8/10

N2 - 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.

AB - 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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ER -

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

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