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.
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.
Department of Chemistry, University of Washington , Seattle, Washington 98195, United States.
Rama Subba Rao
RS
Vidadala
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.
Kasey L
KL
Rivas
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.
Kayode K
KK
Ojo
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.
Matthew A
MA
Hulverson
Paul G. Allen School for Global Animal Health, College of Veterinary Medicine, Washington State University , Pullman, Washington 99164, United States.
Jennifer A
JA
Zambriski
Portland VA Medical Center , Portland, Oregon 97239, United States.
Igor
I
Bruzual
Department of Microbiology and Immunology, University of Michigan Medical School , Ann Arbor, Michigan 48109, United States.
Tracey L
TL
Schultz
Department of Biochemistry, University of Washington , Seattle, Washington 98195, United States.
Wenlin
W
Huang
Department of Biochemistry, University of Washington , Seattle, Washington 98195, United States.
Zhongsheng
Z
Zhang
Center for Infectious Disease Research (formerly Seattle Biomedical Research Institute), Seattle, Washington 98109, United States.
Suzanne
S
Scheele
Center for Infectious Disease Research (formerly Seattle Biomedical Research Institute), Seattle, Washington 98109, United States.
Amy E
AE
DeRocher
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.
Ryan
R
Choi
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.
Lynn K
LK
Barrett
Department of Biochemistry, University of Washington , Seattle, Washington 98195, United States.
Latha Kallur
LK
Siddaramaiah
Department of Biochemistry, University of Washington , Seattle, Washington 98195, United States.
Wim G J
WG
Hol
Department of Biochemistry, University of Washington , Seattle, Washington 98195, United States.
Erkang
E
Fan
Department of Biochemistry, University of Washington , Seattle, Washington 98195, United States.
Ethan A
EA
Merritt
Center for Infectious Disease Research (formerly Seattle Biomedical Research Institute), Seattle, Washington 98109, United States.|Department of Global Health, University of Washington , Seattle, Washington 98195, United States.
Marilyn
M
Parsons
AbbVie , North Chicago, Illinois 60064, United States.
Gail
G
Freiberg
AbbVie , North Chicago, Illinois 60064, United States.
Kennan
K
Marsh
AbbVie , North Chicago, Illinois 60064, United States.
Dale J
DJ
Kempf
Department of Microbiology and Immunology, University of Michigan Medical School , Ann Arbor, Michigan 48109, United States.
Vern B
VB
Carruthers
Department of Pharmaceutics, University of Washington , Seattle, Washington 98195, United States.
Nina
N
Isoherranen
Portland VA Medical Center , Portland, Oregon 97239, United States.
J Stone
JS
Doggett
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.|Department of Global Health, University of Washington , Seattle, Washington 98195, United States.
Wesley C
WC
Van Voorhis
Department of Biochemistry, University of Washington , Seattle, Washington 98195, United States.|Department of Chemistry, University of Washington , Seattle, Washington 98195, United States.
Dustin J
DJ
Maly
D000284:Administration, Oral; D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D002490:Central Nervous System / Q000187:drug effects*; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D000882:Haplorhini; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014122:Toxoplasma / Q000187:drug effects* / Q000201:enzymology; D014123:Toxoplasmosis / Q000188:drug therapy* / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases
D000981:Antiprotozoal Agents; D051638:Ether-A-Go-Go Potassium Channels; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases