title: SAR Studies of 5-Aminopyrazole-4-carboxamide Analogues as Potent and Selective Inhibitors ofToxoplasma gondiiCDPK1.
abstract: We previously discovered compounds based on a 5-aminopyrazole-4-carboxamide scaffold to be potent and selective inhibitors of CDPK1 fromT. gondii. The current work, through structure-activity relationship studies, led to the discovery of compounds (34and35) with improved characteristics over the starting inhibitor1in terms of solubility, plasma exposure after oral administration in mice, or efficacy on parasite growth inhibition. Compounds34and35were further demonstrated to be more effective than1in a mouse infection model and markedly reduced the amount ofT. gondiiin the brain, spleen, and peritoneal fluid, and35given at 20 mg/kg eliminatedT. gondiifrom the peritoneal fluid.
authors.affiliation: Department of Biochemistry, University of Washington , Seattle, Washington 98195, United States.
authors.forename: Wenlin
authors.initials: W
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: Kayode K
authors.initials: KK
authors.lastname: Ojo
authors.affiliation: Department of Biochemistry, University of Washington , Seattle, Washington 98195, United States.
authors.forename: Zhongsheng
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Kasey
authors.initials: K
authors.lastname: Rivas
authors.affiliation: Department of Chemistry, University of Washington , Seattle, Washington 98195, United States.
authors.forename: Rama Subba Rao
authors.initials: RS
authors.lastname: Vidadala
authors.affiliation: Center for Infectious Disease Research (formerly Seattle Biomedical Research Institute), Seattle, Washington 98109, United States.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Scheele
authors.affiliation: Center for Infectious Disease Research (formerly Seattle Biomedical Research Institute), Seattle, Washington 98109, United States.
authors.forename: Amy E
authors.initials: AE
authors.lastname: DeRocher
authors.affiliation: 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.
authors.forename: Ryan
authors.initials: R
authors.lastname: Choi
authors.affiliation: 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.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Hulverson
authors.affiliation: 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.
authors.forename: Lynn K
authors.initials: LK
authors.lastname: Barrett
authors.affiliation: Portland VA Medical Center , Portland, Oregon 97239, United States.
authors.forename: Igor
authors.initials: I
authors.lastname: Bruzual
authors.affiliation: Department of Biochemistry, University of Washington , Seattle, Washington 98195, United States.
authors.forename: Latha Kallur
authors.initials: LK
authors.lastname: Siddaramaiah
authors.affiliation: Department of Biochemistry, University of Washington , Seattle, Washington 98195, United States.
authors.forename: Keshia M
authors.initials: KM
authors.lastname: Kerchner
authors.affiliation: AbbVie , N. Chicago, Illinois 60064, United States.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Kurnick
authors.affiliation: AbbVie , N. Chicago, Illinois 60064, United States.
authors.forename: Gail M
authors.initials: GM
authors.lastname: Freiberg
authors.affiliation: AbbVie , N. Chicago, Illinois 60064, United States.
authors.forename: Dale
authors.initials: D
authors.lastname: Kempf
authors.affiliation: Department of Biochemistry, University of Washington , Seattle, Washington 98195, United States.
authors.forename: Wim G J
authors.initials: WG
authors.lastname: Hol
authors.affiliation: Department of Biochemistry, University of Washington , Seattle, Washington 98195, United States.
authors.forename: Ethan A
authors.initials: EA
authors.lastname: Merritt
authors.affiliation: PATH , San Francisco, California 94102, United States.
authors.forename: Georg
authors.initials: G
authors.lastname: Neckermann
authors.affiliation: PATH , San Francisco, California 94102, United States.
authors.forename: Eugenio L
authors.initials: EL
authors.lastname: de Hostos
authors.affiliation: Department of Pharmaceutics, University of Washington , Seattle, Washington 98195, United States.
authors.forename: Nina
authors.initials: N
authors.lastname: Isoherranen
authors.affiliation: Department of Chemistry, University of Washington , Seattle, Washington 98195, United States.
authors.forename: Dustin J
authors.initials: DJ
authors.lastname: Maly
authors.affiliation: 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.
authors.forename: Marilyn
authors.initials: M
authors.lastname: Parsons
authors.affiliation: Portland VA Medical Center , Portland, Oregon 97239, United States.
authors.forename: J Stone
authors.initials: JS
authors.lastname: Doggett
authors.affiliation: 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.
authors.forename: Wesley C
authors.initials: WC
authors.lastname: Van Voorhis
authors.affiliation: Department of Biochemistry, University of Washington , Seattle, Washington 98195, United States.
authors.forename: Erkang
authors.initials: E
authors.lastname: Fan
keywords: Toxoplasma gondii; calcium-dependent protein kinase-1; enzyme inhibitor; structure−activity relationship studies