Comparison of Toxicities among Different Bumped Kinase Inhibitor Analogs for Treatment of Cryptosporidiosis

Recent advances on the development of bumped kinase inhibitors for treatment of cryptosporidiosis have focused on the 5-aminopyrazole-4-carboxamide scaffold, due to analogs that have less hERG inhibition, superior efficacy, and strong in vitro safety profiles. Three compounds, BKI-1770, -1841, and -1708, showed strong efficacy in C. parvum infected mice. Both BKI-1770 and BKI-1841 had efficacy in the C. parvum newborn calf model, reducing diarrhea and oocyst excretion. However, both compounds caused hyperflexion of the limbs seen as dropped pasterns. Toxicity experiments in rats and calves dosed with BKI-1770 showed enlargement of the epiphyseal growth plate at doses only slightly higher than the efficacious dose. Mice were used as a screen to check for bone toxicity, by changes to the tibia epiphyseal growth plate, or neurological causes, by use of a locomotor activity box. These results showed neurological effects from both BKI-1770 and BKI-1841 and bone toxicity in mice from BKI-1770, indicating one or both effects may be contributing to toxicity. However, BKI-1708 remains a viable treatment candidate for further evaluation as it showed no signs of bone toxicity or neurological effects in mice. Recent advances on the development of bumped kinase inhibitors for treatment of cryptosporidiosis have focused on the 5-aminopyrazole-4-carboxamide scaffold, due to analogs that have less hERG inhibition, superior efficacy, and strong in vitro safety profiles. Three compounds, BKI-1770, -1841, and -1708, showed strong efficacy in C. parvum infected mice.

Automated summary

Recent advances in the development of bumped kinase inhibitors for treating cryptosporidiosis have focused on a specific structure known as 5-aminopyrazole-4-carboxamide scaffold, which has shown superior efficacy, reduced hERG inhibition, and excellent safety profiles in vitro. Three compounds (BKI-1770, -1841, and -1708) demonstrated strong effectiveness in mice infected with C. parvum. While BKI-1770 and BKI-1841 were effective in a C. parvum calf model, they caused limb hyperflexion. Toxicity experiments in rats and calves revealed bone toxicity at slightly higher doses than the efficacious dose for BKI-1770. Both BKI-1770 and BKI-1841 showed neurological effects in mice, and BKI-1770 also displayed bone toxicity. However, BKI-1708 showed no signs of bone toxicity or neurological effects in mice, making it a promising candidate for further evaluation.