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

J Med Chem. 2016 Jul 14;59(13):6531-46. doi: 10.1021/acs.jmedchem.6b00760.

Rama Subba Rao Vidadala ¹, Kasey L Rivas ², Kayode K Ojo ², Matthew A Hulverson ², Jennifer A Zambriski ³, Igor Bruzual ⁴, Tracey L Schultz ⁵, Wenlin Huang ⁶, Zhongsheng Zhang ⁶, Suzanne Scheele ⁷, Amy E DeRocher ⁷, Ryan Choi ², Lynn K Barrett ², Latha Kallur Siddaramaiah ⁶, Wim G J Hol ⁶, Erkang Fan ⁶, Ethan A Merritt ⁶, Marilyn Parsons ⁷ ⁸, Gail Freiberg ⁹, Kennan Marsh ⁹, Dale J Kempf ⁹, Vern B Carruthers ⁵, Nina Isoherranen ¹⁰, J Stone Doggett ⁴, Wesley C Van Voorhis ² ⁸, Dustin J Maly ⁶ ¹

Affiliations

1 Department of Chemistry, University of Washington , Seattle, Washington 98195, United States.
2 Department of Medicine, Division of Allergy and Infectious Diseases, and the Center for Emerging and Re-Emerging Infectious Diseases (CERID), University of Washington , Seattle, Washington 98109, United States.
3 Paul G. Allen School for Global Animal Health, College of Veterinary Medicine, Washington State University , Pullman, Washington 99164, United States.
4 Portland VA Medical Center , Portland, Oregon 97239, United States.
5 Department of Microbiology and Immunology, University of Michigan Medical School , Ann Arbor, Michigan 48109, United States.
6 Department of Biochemistry, University of Washington , Seattle, Washington 98195, United States.
7 Center for Infectious Disease Research (formerly Seattle Biomedical Research Institute), Seattle, Washington 98109, United States.
8 Department of Global Health, University of Washington , Seattle, Washington 98195, United States.
9 AbbVie , North Chicago, Illinois 60064, United States.
10 Department of Pharmaceutics, University of Washington , Seattle, Washington 98195, United States.

PMID: 27309760 DOI: 10.1021/acs.jmedchem.6b00760

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.

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