@article{04f6c8050b9949d1a720453fb3eba8e3,
title = "Comparison of Toxicities among Different Bumped Kinase Inhibitor Analogs for Treatment of Cryptosporidiosis",
abstract = "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.",
keywords = "BKI-1708, BKI-1770, BKI-1841, Cryptosporidium, bumped kinase inhibitors, calcium-dependent protein kinases, cryptosporidiosis, epiphyseal growth plate",
author = "Hulverson, {Matthew A.} and Ryan Choi and Schaefer, {Deborah A.} and Betzer, {Dana P.} and McCloskey, {Molly C.} and Whitman, {Grant R.} and Wenlin Huang and Sangun Lee and Andy Pranata and McLeod, {Malcolm D.} and Marsh, {Kennan C.} and Kempf, {Dale J.} and LeRoy, {Bruce E.} and Zafiratos, {Mark T.} and Bielinski, {Aimee L.} and Hackman, {Robert C.} and Ojo, {Kayode K.} and Arnold, {Samuel L.M.} and Barrett, {Lynn K.} and Saul Tzipori and Riggs, {Michael W.} and Erkang Fan and {Van Voorhis}, {Wesley C.}",
note = "Funding Information: We thank Robert Choy and Eugenio de Hostos from PATH Drug Solutions for their consultation in the drug development pathway, Wayne R. Buck (AbbVie) for consultation on in vivo toxicity testing of BKIs in rat and dog cardiotoxicity and the mouse locomotor activity box, and Gail M. Freiberg (AbbVie) for distributing the compounds and tracking them for the hERG inhibition, in vivo rat and dog cardiotoxicity, hepatocyte metabolite identification, and mouse exploratory activity box experiments. Research studies reported in this publication were supported by National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH), USA, under award numbers R01AI089441, R01AI111341 and R01HD080670. The work was also supported by award number 2014-06183 and ARZT-5704210-A50-133 from the United States Department of Agriculture National Institute of Food and Agriculture and funding from the Bill and Melinda Gates Foundation opportunity/contract ID OPP1132800. Publisher Copyright: Copyright {\textcopyright} 2023 Hulverson et al.",
year = "2023",
month = apr,
doi = "10.1128/aac.01425-22",
language = "English (US)",
volume = "67",
journal = "Antimicrobial Agents and Chemotherapy",
issn = "0066-4804",
publisher = "American Society for Microbiology",
number = "4",
}