6MNY

Aminopyrazole Carboxamide Bruton's Tyrosine Kinase Inhibitors. Irreversible to Reversible Covalent Reactive Group Tuning.

Schnute, M.E., Benoit, S.E., Buchler, I.P., Caspers, N., Grapperhaus, M.L., Han, S., Hotchandani, R., Huang, N., Hughes, R.O., Juba, B.M., Kim, K.H., Liu, E., McCarthy, E., Messing, D., Miyashiro, J.S., Mohan, S., O'Connell, T.N., Ohren, J.F., Parikh, M.D., Schmidt, M., Selness, S.R., Springer, J.R., Thanabal, V., Trujillo, J.I., Walker, D.P., Wan, Z.K., Withka, J.M., Wittwer, A.J., Wood, N.L., Xing, L., Zapf, C.W., Douhan III, J.

(2019) ACS Med Chem Lett 10: 80-85

• PubMed: 30655951 Search on PubMedSearch on PubMed Central
• DOI: https://doi.org/10.1021/acsmedchemlett.8b00461
• Primary Citation of Related Structures:  
  6MNY


• PubMed Abstract: 
  

  Potent covalent inhibitors of Bruton's tyrosine kinase (BTK) based on an aminopyrazole carboxamide scaffold have been identified. Compared to acrylamide-based covalent reactive groups leading to irreversible protein adducts, cyanamide-based reversible-covalent inhibitors provided the highest combined BTK potency and EGFR selectivity. The cyanamide covalent mechanism with BTK was confirmed through enzyme kinetic, NMR, MS, and X-ray crystallographic studies. The lead cyanamide-based inhibitors demonstrated excellent kinome selectivity and rat pharmacokinetic properties.

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Organizational Affiliation: 

Medicine Design and Inflammation and Immunology Research, Pfizer, Cambridge, Massachusetts 02139, United States.