TY - JOUR
T1 - 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
AU - Vidadala, Rama Subba Rao
AU - Rivas, Kasey L.
AU - Ojo, Kayode K.
AU - Hulverson, Matthew A.
AU - Zambriski, Jennifer A.
AU - Bruzual, Igor
AU - Schultz, Tracey L.
AU - Huang, Wenlin
AU - Zhang, Zhongsheng
AU - Scheele, Suzanne
AU - DeRocher, Amy E.
AU - Choi, Ryan
AU - Barrett, Lynn K.
AU - Siddaramaiah, Latha Kallur
AU - Hol, Wim G.J.
AU - Fan, Erkang
AU - Merritt, Ethan A.
AU - Parsons, Marilyn
AU - Freiberg, Gail
AU - Marsh, Kennan
AU - Kempf, Dale J.
AU - Carruthers, Vern B.
AU - Isoherranen, Nina
AU - Doggett, J. Stone
AU - Van Voorhis, Wesley C.
AU - Maly, Dustin J.
N1 - Publisher Copyright:
© 2016 American Chemical Society.
PY - 2016/7/14
Y1 - 2016/7/14
N2 - 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.
AB - 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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U2 - 10.1021/acs.jmedchem.6b00760
DO - 10.1021/acs.jmedchem.6b00760
M3 - Article
C2 - 27309760
AN - SCOPUS:84978476937
SN - 0022-2623
VL - 59
SP - 6531
EP - 6546
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 13
ER -