5-Aminopyrazole-4-carboxamide-based compounds prevent the growth of Cryptosporidium parvum

Wenlin Huang; Ryan Choi; Matthew A. Hulverson; Zhongsheng Zhang; Molly C. McCloskey; Deborah A. Schaefer; Grant R. Whitman; Lynn K. Barrett; Rama Subba Rao Vidadala; Michael W. Riggs; Dustin J. Maly; Wesley C. Van Voorhis; Kayode K. Ojo; Erkang Fan

doi:10.1128/AAC.00020-17

5-Aminopyrazole-4-carboxamide-based compounds prevent the growth of Cryptosporidium parvum

Wenlin Huang, Ryan Choi, Matthew A. Hulverson, Zhongsheng Zhang, Molly C. McCloskey, Deborah A. Schaefer, Grant R. Whitman, Lynn K. Barrett, Rama Subba Rao Vidadala, Michael W. Riggs, Dustin J. Maly, Wesley C. Van Voorhis, Kayode K. Ojo, Erkang Fan

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17 Scopus citations

Abstract

Cryptosporidium parvum calcium-dependent protein kinase 1 (CpCDPK1) is a promising target for drug development against cryptosporidiosis. We report a series of low-nanomolar CpCDPK1 5-aminopyrazole-4-carboxamide (AC) scaffold inhibitors that also potently inhibit C. parvum growth in vitro. Correlation between anti-CpCDPK1 and C. parvum growth inhibition, as previously reported for pyrazolopyrimidines, was not apparent. Nonetheless, lead AC compounds exhibited a substantial reduction of parasite burden in the neonatal mouse cryptosporidiosis model when dosed at 25 mg/kg.

Original language	English (US)
Article number	e00020
Journal	Antimicrobial Agents and Chemotherapy
Volume	61
Issue number	8
DOIs	https://doi.org/10.1128/AAC.00020-17
State	Published - Aug 2017

Keywords

5-aminopyrazole-4-carboxamide
Bumped kinase inhibitors
Cryptosporidium parvum

ASJC Scopus subject areas

Pharmacology
Pharmacology (medical)
Infectious Diseases

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10.1128/AAC.00020-17

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Huang, W., Choi, R., Hulverson, M. A., Zhang, Z., McCloskey, M. C., Schaefer, D. A., Whitman, G. R., Barrett, L. K., Vidadala, R. S. R., Riggs, M. W., Maly, D. J., Van Voorhis, W. C., Ojo, K. K., & Fan, E. (2017). 5-Aminopyrazole-4-carboxamide-based compounds prevent the growth of Cryptosporidium parvum. Antimicrobial Agents and Chemotherapy, 61(8), Article e00020. https://doi.org/10.1128/AAC.00020-17

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title = "5-Aminopyrazole-4-carboxamide-based compounds prevent the growth of Cryptosporidium parvum",

abstract = "Cryptosporidium parvum calcium-dependent protein kinase 1 (CpCDPK1) is a promising target for drug development against cryptosporidiosis. We report a series of low-nanomolar CpCDPK1 5-aminopyrazole-4-carboxamide (AC) scaffold inhibitors that also potently inhibit C. parvum growth in vitro. Correlation between anti-CpCDPK1 and C. parvum growth inhibition, as previously reported for pyrazolopyrimidines, was not apparent. Nonetheless, lead AC compounds exhibited a substantial reduction of parasite burden in the neonatal mouse cryptosporidiosis model when dosed at 25 mg/kg.",

keywords = "5-aminopyrazole-4-carboxamide, Bumped kinase inhibitors, Cryptosporidium parvum",

author = "Wenlin Huang and Ryan Choi and Hulverson, {Matthew A.} and Zhongsheng Zhang and McCloskey, {Molly C.} and Schaefer, {Deborah A.} and Whitman, {Grant R.} and Barrett, {Lynn K.} and Vidadala, {Rama Subba Rao} and Riggs, {Michael W.} and Maly, {Dustin J.} and {Van Voorhis}, {Wesley C.} and Ojo, {Kayode K.} and Erkang Fan",

year = "2017",

month = aug,

doi = "10.1128/AAC.00020-17",

language = "English (US)",

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journal = "Antimicrobial Agents and Chemotherapy",

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publisher = "American Society for Microbiology",

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AU - Huang, Wenlin

AU - Choi, Ryan

AU - Hulverson, Matthew A.

AU - Zhang, Zhongsheng

AU - McCloskey, Molly C.

AU - Schaefer, Deborah A.

AU - Whitman, Grant R.

AU - Barrett, Lynn K.

AU - Vidadala, Rama Subba Rao

AU - Riggs, Michael W.

AU - Maly, Dustin J.

AU - Van Voorhis, Wesley C.

AU - Ojo, Kayode K.

AU - Fan, Erkang

PY - 2017/8

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AB - Cryptosporidium parvum calcium-dependent protein kinase 1 (CpCDPK1) is a promising target for drug development against cryptosporidiosis. We report a series of low-nanomolar CpCDPK1 5-aminopyrazole-4-carboxamide (AC) scaffold inhibitors that also potently inhibit C. parvum growth in vitro. Correlation between anti-CpCDPK1 and C. parvum growth inhibition, as previously reported for pyrazolopyrimidines, was not apparent. Nonetheless, lead AC compounds exhibited a substantial reduction of parasite burden in the neonatal mouse cryptosporidiosis model when dosed at 25 mg/kg.

KW - 5-aminopyrazole-4-carboxamide

KW - Bumped kinase inhibitors

KW - Cryptosporidium parvum

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ER -

5-Aminopyrazole-4-carboxamide-based compounds prevent the growth of Cryptosporidium parvum

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Keywords

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