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

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.