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

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.

SUBMITTER: Schnute ME 

PROVIDER: S-EPMC6331194 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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

Schnute Mark E ME   Benoit Stephen E SE   Buchler Ingrid P IP   Caspers Nicole N   Grapperhaus Margaret L ML   Han Seungil S   Hotchandani Rajeev R   Huang Nelson N   Hughes Robert O RO   Juba Brian M BM   Kim Kyung-Hee KH   Liu Erica E   McCarthy Erin E   Messing Dean D   Miyashiro Joy S JS   Mohan Shashi S   O'Connell Thomas N TN   Ohren Jeffrey F JF   Parikh Mihir D MD   Schmidt Michelle M   Selness Shaun R SR   Springer John R JR   Thanabal Venkataraman V   Trujillo John I JI   Walker Daniel P DP   Wan Zhao-Kui ZK   Withka Jane M JM   Wittwer Arthur J AJ   Wood Nancy L NL   Xing Li L   Zapf Christoph W CW   Douhan John J  

ACS medicinal chemistry letters 20181203 1

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 dem  ...[more]

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