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

Yang Zheng; Magali van den Kerkhof; Mohamed Ibrahim; Iwan J.P. De Esch; Louis Maes; Geert Jan Sterk; Guy Caljon; Rob Leurs

doi:10.1021/acs.jmedchem.3c01976

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

Yang Zheng
, Magali van den Kerkhof
, Mohamed Ibrahim
, Iwan J.P. De Esch
, 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) still faces few therapeutic options and emerging drug resistance, stressing an urgency for novel antitrypanosomal drug discovery. Here, we describe lead optimization efforts aiming at improving antitrypanosomal efficacy and better physicochemical properties based on our previously reported optimized hit NPD-2975 (pIC₅₀ 7.2). Systematic modification of the 5-phenylpyrazolopyrimidinone NPD-2975 led to the discovery of a R₄-substituted analogue 31c (NPD-3519), showing higher in vitro potency (pIC₅₀ 7.8) against Trypanosoma brucei and significantly better metabolic stability. Further, in vivo pharmacokinetic evaluation of 31c and experiments in an acute T. brucei mouse model confirmed improved oral bioavailability and antitrypanosomal efficacy at 50 mg/kg with no apparent toxicity. With good physicochemical properties, low toxicity, improved pharmacokinetic features, and in vivo efficacy, 31c may serve as a promising candidate for future drug development for HAT.

Original language	English
Pages (from-to)	2849-2863
Number of pages	15
Journal	Journal of medicinal chemistry
Volume	67
Issue number	4
Early online date	8 Feb 2024
DOIs	https://doi.org/10.1021/acs.jmedchem.3c01976
Publication status	Published - 22 Feb 2024

Bibliographical note

Publisher Copyright:
© 2024 The Authors. Published by American Chemical Society.

Funding

Lady Bautista, Odessa Visser, and Lars Binkhorst are thanked for their synthetic assistance. Hans Custers, Andrea van de Stolpe, Natascha Van Pelt, 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 7th Framework Program FP7-HEALTH-2013-INNOVATION-1 under project reference 602666 “Parasite-specific cyclic nucleotide phosphodiesterase inhibitors to target Neglected Parasitic Diseases” (PDE4NPD). Y.Z. 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. Lady Bautista, Odessa Visser, and Lars Binkhorst are thanked for their synthetic assistance. Hans Custers, Andrea van de Stolpe, Natascha Van Pelt, 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 7th Framework Program FP7-HEALTH-2013-INNOVATION-1 under project reference 602666 “Parasite-specific cyclic nucleotide phosphodiesterase inhibitors to target Neglected Parasitic Diseases” (PDE4NPD). Y.Z. 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.

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

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title = "Lead Optimization of the 5-Phenylpyrazolopyrimidinone NPD-2975 toward Compounds with Improved Antitrypanosomal Efficacy",

abstract = "Human African trypanosomiasis (HAT) still faces few therapeutic options and emerging drug resistance, stressing an urgency for novel antitrypanosomal drug discovery. Here, we describe lead optimization efforts aiming at improving antitrypanosomal efficacy and better physicochemical properties based on our previously reported optimized hit NPD-2975 (pIC50 7.2). Systematic modification of the 5-phenylpyrazolopyrimidinone NPD-2975 led to the discovery of a R4-substituted analogue 31c (NPD-3519), showing higher in vitro potency (pIC50 7.8) against Trypanosoma brucei and significantly better metabolic stability. Further, in vivo pharmacokinetic evaluation of 31c and experiments in an acute T. brucei mouse model confirmed improved oral bioavailability and antitrypanosomal efficacy at 50 mg/kg with no apparent toxicity. With good physicochemical properties, low toxicity, improved pharmacokinetic features, and in vivo efficacy, 31c may serve as a promising candidate for future drug development for HAT.",

author = "Yang Zheng and \{van den Kerkhof\}, Magali and Mohamed Ibrahim and \{De Esch\}, \{Iwan J.P.\} and Louis Maes and Sterk, \{Geert Jan\} and Guy Caljon and Rob Leurs",

note = "Publisher Copyright: {\textcopyright} 2024 The Authors. Published by American Chemical Society.",

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doi = "10.1021/acs.jmedchem.3c01976",

language = "English",

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AU - Zheng, Yang

AU - van den Kerkhof, Magali

AU - Ibrahim, Mohamed

AU - De Esch, Iwan J.P.

AU - Maes, Louis

AU - Sterk, Geert Jan

AU - Caljon, Guy

AU - Leurs, Rob

PY - 2024/2/22

Y1 - 2024/2/22

N2 - Human African trypanosomiasis (HAT) still faces few therapeutic options and emerging drug resistance, stressing an urgency for novel antitrypanosomal drug discovery. Here, we describe lead optimization efforts aiming at improving antitrypanosomal efficacy and better physicochemical properties based on our previously reported optimized hit NPD-2975 (pIC50 7.2). Systematic modification of the 5-phenylpyrazolopyrimidinone NPD-2975 led to the discovery of a R4-substituted analogue 31c (NPD-3519), showing higher in vitro potency (pIC50 7.8) against Trypanosoma brucei and significantly better metabolic stability. Further, in vivo pharmacokinetic evaluation of 31c and experiments in an acute T. brucei mouse model confirmed improved oral bioavailability and antitrypanosomal efficacy at 50 mg/kg with no apparent toxicity. With good physicochemical properties, low toxicity, improved pharmacokinetic features, and in vivo efficacy, 31c may serve as a promising candidate for future drug development for HAT.

AB - Human African trypanosomiasis (HAT) still faces few therapeutic options and emerging drug resistance, stressing an urgency for novel antitrypanosomal drug discovery. Here, we describe lead optimization efforts aiming at improving antitrypanosomal efficacy and better physicochemical properties based on our previously reported optimized hit NPD-2975 (pIC50 7.2). Systematic modification of the 5-phenylpyrazolopyrimidinone NPD-2975 led to the discovery of a R4-substituted analogue 31c (NPD-3519), showing higher in vitro potency (pIC50 7.8) against Trypanosoma brucei and significantly better metabolic stability. Further, in vivo pharmacokinetic evaluation of 31c and experiments in an acute T. brucei mouse model confirmed improved oral bioavailability and antitrypanosomal efficacy at 50 mg/kg with no apparent toxicity. With good physicochemical properties, low toxicity, improved pharmacokinetic features, and in vivo efficacy, 31c may serve as a promising candidate for future drug development for HAT.

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

Abstract

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Funding

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