氨基吡唑甲酰胺类布鲁顿酪氨酸激酶抑制剂。从不可逆到可逆的共价反应基团调控
Aminopyrazole Carboxamide Bruton's Tyrosine Kinase Inhibitors. Irreversible to Reversible Covalent Reactive Group Tuning.
作者信息
Schnute Mark E, Benoit Stephen E, Buchler Ingrid P, Caspers Nicole, Grapperhaus Margaret L, Han Seungil, Hotchandani Rajeev, Huang Nelson, Hughes Robert O, Juba Brian M, Kim Kyung-Hee, Liu Erica, McCarthy Erin, Messing Dean, Miyashiro Joy S, Mohan Shashi, O'Connell Thomas N, Ohren Jeffrey F, Parikh Mihir D, Schmidt Michelle, Selness Shaun R, Springer John R, Thanabal Venkataraman, Trujillo John I, Walker Daniel P, Wan Zhao-Kui, Withka Jane M, Wittwer Arthur J, Wood Nancy L, Xing Li, Zapf Christoph W, Douhan John
机构信息
Medicine Design and Inflammation and Immunology Research, Pfizer, Cambridge, Massachusetts 02139, United States.
Medicine Design, Pfizer, Groton, Connecticut 06340, United States.
出版信息
ACS Med Chem Lett. 2018 Dec 3;10(1):80-85. doi: 10.1021/acsmedchemlett.8b00461. eCollection 2019 Jan 10.
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.
摘要
已鉴定出基于氨基吡唑甲酰胺支架的布鲁顿酪氨酸激酶（BTK）的强效共价抑制剂。与导致不可逆蛋白质加合物的基于丙烯酰胺的共价反应基团相比，基于氰胺的可逆共价抑制剂具有最高的BTK效力和EGFR选择性组合。通过酶动力学、核磁共振、质谱和X射线晶体学研究证实了氰胺与BTK的共价机制。基于氰胺的先导抑制剂表现出优异的激酶组选择性和大鼠药代动力学特性。
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