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

Abstract

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-4carboxamide-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 pre-clinical leads for cryptosporidiosis therapy with acceptable safety parameters and efficacy in the mouse model of cryptosporidiosis.

Comparative assessment of the effects of bumped kinase inhibitors on early zebrafish embryo development and pregnancy in mice

“…Recently BKI-1294 treatment was applied in pregnant sheep experimentally infected with T. gondii oocysts where it was partially efficacious against T. gondii infection, and no adverse effects of drug treatment were noted in this small ruminant model [36]. BKI-1369 and BKI-1770 are lead compounds for the treatment of diarrhea caused by cryptosporidiosis in calves [15,17]. In addition, excellent BKI-1369 efficacy was demonstrated against Cystisospora suis infection in piglets [18], and in a pig model of acute diarrhea caused by Cryptosporidium hominis ([16].…”

“…BKIs have proven in vitro activity against Babesia bovis [6] and Besnoitia besnoiti [10], as well as in vitro and in vivo against Cryptosporidium spp. [11–17], Cystoisospora suis [18], T. gondii [19–21] and N. caninum [21–23]. Despite promising efficacies, some BKIs have shown toxicity in vivo .…”

In vitro activity, safety and in vivo efficacy of the novel bumped kinase inhibitor BKI-1748 in non-pregnant and pregnant mice experimentally infected with Neospora caninum tachyzoites and Toxoplasma gondii oocysts

“…BKI-1748 has a number of attractive efficacy and safety features. It inhibits Tg CDPK1 and Nc CDPK1 enzyme activities at low nM-concentrations and has excellent pharmacokinetics after oral dosing with 25 mg/kg in mice, achieving 38.6 μM maximum concentration with an area-under-the-curve of 11412 min*μmol/L and half-life of 164 min, allowing once daily-dosing ( Huang et al, 2019 ). Solubility is > 100 μM in aqueous solution at pH 6.5 and 2.0, and BKI-1748 is only 80% mouse-plasma-bound ( Huang et al, 2019 ).…”

Plasmodial Kinase Inhibitors Targeting Malaria: Recent Developments

“…17 was selective as it possessed an IC 50 superior to 30 µM against Hs SRC. Work on this series is currently focused on C. parvum therapy [ 40 ].…”