Mark E Schnute, Stephen E Benoit, Ingrid P Buchler, Nicole Caspers, Margaret L Grapperhaus, Seungil Han, Rajeev Hotchandani, Nelson Huang, Robert O Hughes, Brian M Juba, Kyung-Hee Kim, Erica Liu, Erin McCarthy, Dean Messing, Joy S Miyashiro, Shashi Mohan, Thomas N O'Connell, Jeffrey F Ohren, Mihir D Parikh, Michelle Schmidt, Shaun R Selness, John R Springer, Venkataraman Thanabal, John I Trujillo, Daniel P Walker, Zhao-Kui Wan, Jane M Withka, Arthur J Wittwer, Nancy L Wood, Li Xing, Christoph W Zapf, John Douhan
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...
January 10, 2019: ACS Medicinal Chemistry Letters