Pharmacokinetics and In Vivo Efficacy of Pyrazolopyrimidine, Pyrrolopyrimidine, and 5-Aminopyrazole-4-Carboxamide Bumped Kinase Inhibitors against Toxoplasmosis

Matthew A. Hulverson, Igor Bruzual, Erin V. McConnell, Wenlin Huang, Rama S.R. Vidadala, Ryan Choi, Samuel L.M. Arnold, Grant R. Whitman, Molly C. McCloskey, Lynn K. Barrett, Kasey L. Rivas, Suzanne Scheele, Amy E. DeRocher, Marilyn Parsons, Kayode K. Ojo, Dustin J. Maly, Erkang Fan, Wesley C. Van Voorhis, Joseph Doggett

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1464-1473
Number of pages10
JournalThe Journal of infectious diseases
Volume219
Issue number9
DOIs
StatePublished - Apr 16 2019
Externally publishedYes

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Toxoplasmosis
Phosphotransferases
Pharmacokinetics
Toxoplasma
Poisons
5-aminopyrazole
pyrrolopyrimidine
Theoretical Models
Therapeutics

Keywords

  • Toxoplasma gondii
  • bumped kinase inhibitors
  • calcium-dependent protein kinase 1
  • toxoplasmosis treatment

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases

Cite this

Pharmacokinetics and In Vivo Efficacy of Pyrazolopyrimidine, Pyrrolopyrimidine, and 5-Aminopyrazole-4-Carboxamide Bumped Kinase Inhibitors against Toxoplasmosis. / Hulverson, Matthew A.; Bruzual, Igor; McConnell, Erin V.; Huang, Wenlin; Vidadala, Rama S.R.; Choi, Ryan; Arnold, Samuel L.M.; Whitman, Grant R.; McCloskey, Molly C.; Barrett, Lynn K.; Rivas, Kasey L.; Scheele, Suzanne; DeRocher, Amy E.; Parsons, Marilyn; Ojo, Kayode K.; Maly, Dustin J.; Fan, Erkang; Van Voorhis, Wesley C.; Doggett, Joseph.

In: The Journal of infectious diseases, Vol. 219, No. 9, 16.04.2019, p. 1464-1473.

Research output: Contribution to journalArticle

Hulverson, MA, Bruzual, I, McConnell, EV, Huang, W, Vidadala, RSR, Choi, R, Arnold, SLM, Whitman, GR, McCloskey, MC, Barrett, LK, Rivas, KL, Scheele, S, DeRocher, AE, Parsons, M, Ojo, KK, Maly, DJ, Fan, E, Van Voorhis, WC & Doggett, J 2019, 'Pharmacokinetics and In Vivo Efficacy of Pyrazolopyrimidine, Pyrrolopyrimidine, and 5-Aminopyrazole-4-Carboxamide Bumped Kinase Inhibitors against Toxoplasmosis', The Journal of infectious diseases, vol. 219, no. 9, pp. 1464-1473. https://doi.org/10.1093/infdis/jiy664
Hulverson, Matthew A. ; Bruzual, Igor ; McConnell, Erin V. ; Huang, Wenlin ; Vidadala, Rama S.R. ; Choi, Ryan ; Arnold, Samuel L.M. ; Whitman, Grant R. ; McCloskey, Molly C. ; Barrett, Lynn K. ; Rivas, Kasey L. ; Scheele, Suzanne ; DeRocher, Amy E. ; Parsons, Marilyn ; Ojo, Kayode K. ; Maly, Dustin J. ; Fan, Erkang ; Van Voorhis, Wesley C. ; Doggett, Joseph. / Pharmacokinetics and In Vivo Efficacy of Pyrazolopyrimidine, Pyrrolopyrimidine, and 5-Aminopyrazole-4-Carboxamide Bumped Kinase Inhibitors against Toxoplasmosis. In: The Journal of infectious diseases. 2019 ; Vol. 219, No. 9. pp. 1464-1473.
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AU - Maly, Dustin J.

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AU - Doggett, Joseph

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