Development of 5-Aminopyrazole-4-carboxamide-based Bumped-Kinase Inhibitors for Cryptosporidiosis Therapy.

Autor:	Huang W, Hulverson MA; Department of Medicine, Division of Allergy & Infectious Disease, Center for Emerging & Re-Emerging Infectious Disease (CERID) , University of Washington , Seattle , Washington 98109 , United States., Choi R; Department of Medicine, Division of Allergy & Infectious Disease, Center for Emerging & Re-Emerging Infectious Disease (CERID) , University of Washington , Seattle , Washington 98109 , United States., Arnold SLM; Department of Medicine, Division of Allergy & Infectious Disease, Center for Emerging & Re-Emerging Infectious Disease (CERID) , University of Washington , Seattle , Washington 98109 , United States., Zhang Z, McCloskey MC; Department of Medicine, Division of Allergy & Infectious Disease, Center for Emerging & Re-Emerging Infectious Disease (CERID) , University of Washington , Seattle , Washington 98109 , United States., Whitman GR; Department of Medicine, Division of Allergy & Infectious Disease, Center for Emerging & Re-Emerging Infectious Disease (CERID) , University of Washington , Seattle , Washington 98109 , United States., Hackman RC; Fred Hutchinson Cancer Research Center , Seattle , Washington 98109 , United States., Rivas KL; Department of Medicine, Division of Allergy & Infectious Disease, Center for Emerging & Re-Emerging Infectious Disease (CERID) , University of Washington , Seattle , Washington 98109 , United States., Barrett LK; Department of Medicine, Division of Allergy & Infectious Disease, Center for Emerging & Re-Emerging Infectious Disease (CERID) , University of Washington , Seattle , Washington 98109 , United States., Ojo KK; Department of Medicine, Division of Allergy & Infectious Disease, Center for Emerging & Re-Emerging Infectious Disease (CERID) , University of Washington , Seattle , Washington 98109 , United States., Van Voorhis WC; Department of Medicine, Division of Allergy & Infectious Disease, Center for Emerging & Re-Emerging Infectious Disease (CERID) , University of Washington , Seattle , Washington 98109 , United States., Fan E
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2019 Mar 28; Vol. 62 (6), pp. 3135-3146. Date of Electronic Publication: 2019 Mar 15.
DOI:	10.1021/acs.jmedchem.9b00069
Abstrakt:	Cryptosporidium is a leading cause of pediatric diarrhea worldwide. Currently, there is neither a vaccine nor a consistently effective drug available for this disease. Selective 5-aminopyrazole-4-carboxamide-based bumped-kinase inhibitors (BKIs) are effective in both in vitro and in vivo models of Cryptosporidium parvum. Potential cardiotoxicity in some BKIs led to the continued exploration of the 5-aminopyrazole-4-carboxamide scaffold to find safe and effective drug candidates for Cryptosporidium. A series of newly designed BKIs were tested for efficacy against C. parvum using in vitro and in vivo (mouse infection model) assays and safety issues. Compound 6 (BKI 1708) was found to be efficacious at 8 mg/kg dosed once daily (QD) for 5 days with no observable signs of toxicity up to 200 mg/kg dosed QD for 7 days. Compound 15 (BKI 1770) was found to be efficacious at 30 mg/kg dosed twice daily (BID) for 5 days with no observable signs of toxicity up to 300 mg/kg dosed QD for 7 days. Compounds 6 and 15 are promising preclinical leads for cryptosporidiosis therapy with acceptable safety parameters and efficacy in the mouse model of cryptosporidiosis.
Databáze:	MEDLINE
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