| Literature DB >> 27309760 |
Rama Subba Rao Vidadala1, Kasey L Rivas2, Kayode K Ojo2, Matthew A Hulverson2, Jennifer A Zambriski3, Igor Bruzual4, Tracey L Schultz5, Wenlin Huang6, Zhongsheng Zhang6, Suzanne Scheele7, Amy E DeRocher7, Ryan Choi2, Lynn K Barrett2, Latha Kallur Siddaramaiah6, Wim G J Hol6, Erkang Fan6, Ethan A Merritt6, Marilyn Parsons7,8, Gail Freiberg9, Kennan Marsh9, Dale J Kempf9, Vern B Carruthers5, Nina Isoherranen10, J Stone Doggett4, Wesley C Van Voorhis2,8, Dustin J Maly6,1.
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.Entities:
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Year: 2016 PMID： 27309760 PMCID： PMC5100899 DOI： 10.1021/acs.jmedchem.6b00760
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446