Pharmacokinetics and In Vivo Efficacy of Pyrazolopyrimidine, Pyrrolopyrimidine, and 5-Aminopyrazole-4-Carboxamide Bumped Kinase Inhibitors against Toxoplasmosis.
Toxoplasma gondii
bumped kinase inhibitors
calcium-dependent protein kinase 1
toxoplasmosis treatment
Journal
The Journal of infectious diseases
ISSN: 1537-6613
Titre abrégé: J Infect Dis
Pays: United States
ID NLM: 0413675
Informations de publication
Date de publication:
16 04 2019
16 04 2019
Historique:
received:
03
10
2018
accepted:
12
11
2018
pubmed:
14
11
2018
medline:
10
1
2020
entrez:
14
11
2018
Statut:
ppublish
Résumé
Bumped kinase inhibitors (BKIs) have been shown to be potent inhibitors of Toxoplasma gondii calcium-dependent protein kinase 1. Pyrazolopyrimidine and 5-aminopyrazole-4-carboxamide scaffold-based BKIs are effective in acute and chronic experimental models of toxoplasmosis. Through further exploration of these 2 scaffolds and a new pyrrolopyrimidine scaffold, additional compounds have been identified that are extremely effective against acute experimental toxoplasmosis. The in vivo efficacy of these BKIs demonstrates that the cyclopropyloxynaphthyl, cyclopropyloxyquinoline, and 2-ethoxyquinolin-6-yl substituents are associated with efficacy across scaffolds. In addition, a broad range of plasma concentrations after oral dosing resulted from small structural changes to the BKIs. These select BKIs include anti-Toxoplasma compounds that are effective against acute experimental toxoplasmosis and are not toxic in human cell assays, nor to mice when administered for therapy. The BKIs described here are promising late leads for improving anti-Toxoplasma therapy.
Identifiants
pubmed: 30423128
pii: 5180518
doi: 10.1093/infdis/jiy664
pmc: PMC6467197
doi:
Substances chimiques
Protein Kinase Inhibitors
0
Protozoan Proteins
0
Pyrazoles
0
Pyrimidines
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1464-1473Subventions
Organisme : NICHD NIH HHS
ID : R01 HD080670
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI089441
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI112427
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI111341
Pays : United States
Organisme : BLRD VA
ID : IK2 BX002440
Pays : United States
Organisme : NIAID NIH HHS
ID : R21 AI123690
Pays : United States
Informations de copyright
Published by Oxford University Press for the Infectious Diseases Society of America 2018.
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