Related Experiment Videos
Aminopyrazole Carboxamide Bruton's Tyrosine Kinase Inhibitors. Irreversible to Reversible Covalent Reactive Group
Mark E Schnute1, Stephen E Benoit1, Ingrid P Buchler1
1Medicine Design and Inflammation and Immunology Research, Pfizer, Cambridge, Massachusetts 02139, United States.
ACS Medicinal Chemistry Letters
|January 19, 2019
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.