Development of an Orally Available and Central Nervous System (CNS) Penetrant Toxoplasma gondii Calcium-Dependent Protein Kinase 1 (TgCDPK1) Inhibitor with Minimal Human Ether-a-go-go-Related Gene (hERG) Activity for the Treatment of Toxoplasmosis

Rama Subba Rao Vidadala, Kasey L. Rivas, Kayode K. Ojo, Matthew A. Hulverson, Jennifer A. Zambriski, Igor Bruzual, Tracey L. Schultz, Wenlin Huang, Zhongsheng Zhang, Suzanne Scheele, Amy E. DeRocher, Ryan Choi, Lynn K. Barrett, Latha Kallur Siddaramaiah, Wim G J Hol, Erkang Fan, Ethan A. Merritt, Marilyn Parsons, Gail Freiberg, Kennan Marsh & 6 others Dale J. Kempf, Vern B. Carruthers, Nina Isoherranen, Joseph Doggett, Wesley C. Van Voorhis, Dustin J. Maly

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

New therapies are needed for the treatment of toxoplasmosis, which is a disease caused by the protozoan parasite Toxoplasma gondii. To this end, we previously developed a potent and selective inhibitor (compound 1) of Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) that possesses antitoxoplasmosis activity in vitro and in vivo. Unfortunately, 1 has potent human ether-a-go-go-related gene (hERG) inhibitory activity, associated with long Q-T syndrome, and consequently presents a cardiotoxicity risk. Here, we describe the identification of an optimized TgCDPK1 inhibitor 32, which does not have a hERG liability and possesses a favorable pharmacokinetic profile in small and large animals. 32 is CNS-penetrant and highly effective in acute and latent mouse models of T. gondii infection, significantly reducing the amount of parasite in the brain, spleen, and peritoneal fluid and reducing brain cysts by >85%. These properties make 32 a promising lead for the development of a new antitoxoplasmosis therapy.

Original languageEnglish (US)
Pages (from-to)6531-6546
Number of pages16
JournalJournal of Medicinal Chemistry
Volume59
Issue number13
DOIs
StatePublished - Jul 14 2016
Externally publishedYes

Fingerprint

Toxoplasmosis
Toxoplasma
Protein Kinase Inhibitors
Ether
Central Nervous System
Parasites
Genes
Ascitic Fluid
Brain
Cysts
Therapeutics
Spleen
Pharmacokinetics
calcium-dependent protein kinase

ASJC Scopus subject areas

  • Medicine(all)
  • Molecular Medicine
  • Drug Discovery

Cite this

Development of an Orally Available and Central Nervous System (CNS) Penetrant Toxoplasma gondii Calcium-Dependent Protein Kinase 1 (TgCDPK1) Inhibitor with Minimal Human Ether-a-go-go-Related Gene (hERG) Activity for the Treatment of Toxoplasmosis. / Vidadala, Rama Subba Rao; Rivas, Kasey L.; Ojo, Kayode K.; Hulverson, Matthew A.; Zambriski, Jennifer A.; Bruzual, Igor; Schultz, Tracey L.; Huang, Wenlin; Zhang, Zhongsheng; Scheele, Suzanne; DeRocher, Amy E.; Choi, Ryan; Barrett, Lynn K.; Siddaramaiah, Latha Kallur; Hol, Wim G J; Fan, Erkang; Merritt, Ethan A.; Parsons, Marilyn; Freiberg, Gail; Marsh, Kennan; Kempf, Dale J.; Carruthers, Vern B.; Isoherranen, Nina; Doggett, Joseph; Van Voorhis, Wesley C.; Maly, Dustin J.

In: Journal of Medicinal Chemistry, Vol. 59, No. 13, 14.07.2016, p. 6531-6546.

Research output: Contribution to journalArticle

Vidadala, RSR, Rivas, KL, Ojo, KK, Hulverson, MA, Zambriski, JA, Bruzual, I, Schultz, TL, Huang, W, Zhang, Z, Scheele, S, DeRocher, AE, Choi, R, Barrett, LK, Siddaramaiah, LK, Hol, WGJ, Fan, E, Merritt, EA, Parsons, M, Freiberg, G, Marsh, K, Kempf, DJ, Carruthers, VB, Isoherranen, N, Doggett, J, Van Voorhis, WC & Maly, DJ 2016, 'Development of an Orally Available and Central Nervous System (CNS) Penetrant Toxoplasma gondii Calcium-Dependent Protein Kinase 1 (TgCDPK1) Inhibitor with Minimal Human Ether-a-go-go-Related Gene (hERG) Activity for the Treatment of Toxoplasmosis', Journal of Medicinal Chemistry, vol. 59, no. 13, pp. 6531-6546. https://doi.org/10.1021/acs.jmedchem.6b00760
Vidadala, Rama Subba Rao ; Rivas, Kasey L. ; Ojo, Kayode K. ; Hulverson, Matthew A. ; Zambriski, Jennifer A. ; Bruzual, Igor ; Schultz, Tracey L. ; Huang, Wenlin ; Zhang, Zhongsheng ; Scheele, Suzanne ; DeRocher, Amy E. ; Choi, Ryan ; Barrett, Lynn K. ; Siddaramaiah, Latha Kallur ; Hol, Wim G J ; Fan, Erkang ; Merritt, Ethan A. ; Parsons, Marilyn ; Freiberg, Gail ; Marsh, Kennan ; Kempf, Dale J. ; Carruthers, Vern B. ; Isoherranen, Nina ; Doggett, Joseph ; Van Voorhis, Wesley C. ; Maly, Dustin J. / Development of an Orally Available and Central Nervous System (CNS) Penetrant Toxoplasma gondii Calcium-Dependent Protein Kinase 1 (TgCDPK1) Inhibitor with Minimal Human Ether-a-go-go-Related Gene (hERG) Activity for the Treatment of Toxoplasmosis. In: Journal of Medicinal Chemistry. 2016 ; Vol. 59, No. 13. pp. 6531-6546.
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