%0 Journal Article
%T Aminopyrazole Carboxamide Bruton¡¯s Tyrosine Kinase Inhibitors. Irreversible to Reversible Covalent Reactive Group Tuning
%J -
%D 2019
%R https://doi.org/10.1021/acsmedchemlett.8b00461
%X 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
%U https://pubs.acs.org/doi/10.1021/acsmedchemlett.8b00461