| Structural highlights
Publication Abstract from PubMed
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.
Aminopyrazole Carboxamide Bruton's Tyrosine Kinase Inhibitors. Irreversible to Reversible Covalent Reactive Group Tuning.,Schnute ME, Benoit SE, Buchler IP, Caspers N, Grapperhaus ML, Han S, Hotchandani R, Huang N, Hughes RO, Juba BM, Kim KH, Liu E, McCarthy E, Messing D, Miyashiro JS, Mohan S, O'Connell TN, Ohren JF, Parikh MD, Schmidt M, Selness SR, Springer JR, Thanabal V, Trujillo JI, Walker DP, Wan ZK, Withka JM, Wittwer AJ, Wood NL, Xing L, Zapf CW, Douhan J 3rd ACS Med Chem Lett. 2018 Dec 3;10(1):80-85. doi: 10.1021/acsmedchemlett.8b00461., eCollection 2019 Jan 10. PMID:30655951[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Schnute ME, Benoit SE, Buchler IP, Caspers N, Grapperhaus ML, Han S, Hotchandani R, Huang N, Hughes RO, Juba BM, Kim KH, Liu E, McCarthy E, Messing D, Miyashiro JS, Mohan S, O'Connell TN, Ohren JF, Parikh MD, Schmidt M, Selness SR, Springer JR, Thanabal V, Trujillo JI, Walker DP, Wan ZK, Withka JM, Wittwer AJ, Wood NL, Xing L, Zapf CW, Douhan J 3rd. Aminopyrazole Carboxamide Bruton's Tyrosine Kinase Inhibitors. Irreversible to Reversible Covalent Reactive Group Tuning. ACS Med Chem Lett. 2018 Dec 3;10(1):80-85. doi: 10.1021/acsmedchemlett.8b00461., eCollection 2019 Jan 10. PMID:30655951 doi:http://dx.doi.org/10.1021/acsmedchemlett.8b00461
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