Publication
Title
Lead optimization of the 5-phenylpyrazolopyrimidinone NPD-2975 toward compounds with improved antitrypanosomal efficacy
Author
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.
Language
English
Source (journal)
Journal of medicinal chemistry. - Washington, D.C., 1963, currens
Publication
Washington, D.C. : 2024
ISSN
0022-2623 [print]
1520-4804 [online]
DOI
10.1021/ACS.JMEDCHEM.3C01976
Volume/pages
67 :4 (2024) , p. 2849-2863
ISI
001167210700001
Pubmed ID
38330051
Full text (Publisher's DOI)
Full text (open access)
UAntwerpen
Faculty/Department
Research group
Project info
Parasite-specific cyclic nucleotide phosphodiesterase inhibitors to target Neglected Parasitic Diseases (PDE4NPD).
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Record
Identifier
Creation 27.02.2024
Last edited 10.04.2024
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