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

Autor:	Schnute ME; Medicine Design and Inflammation and Immunology Research, Pfizer, Cambridge, Massachusetts 02139, United States., Benoit SE; Medicine Design and Inflammation and Immunology Research, Pfizer, Cambridge, Massachusetts 02139, United States., Buchler IP; Medicine Design and Inflammation and Immunology Research, Pfizer, Cambridge, Massachusetts 02139, United States., Caspers N; Medicine Design, Pfizer, Groton, Connecticut 06340, United States., Grapperhaus ML; Medicinal Chemistry and Inflammation and Immunology Research, Pfizer, St. Louis, Missouri 63017, United States., Han S; Medicine Design, Pfizer, Groton, Connecticut 06340, United States., Hotchandani R; Medicine Design and Inflammation and Immunology Research, Pfizer, Cambridge, Massachusetts 02139, United States., Huang N; Medicine Design and Inflammation and Immunology Research, Pfizer, Cambridge, Massachusetts 02139, United States., Hughes RO; Medicine Design and Inflammation and Immunology Research, Pfizer, Cambridge, Massachusetts 02139, United States., Juba BM; Medicine Design and Inflammation and Immunology Research, Pfizer, Cambridge, Massachusetts 02139, United States., Kim KH; Medicine Design and Inflammation and Immunology Research, Pfizer, Cambridge, Massachusetts 02139, United States., Liu E; Medicine Design and Inflammation and Immunology Research, Pfizer, Cambridge, Massachusetts 02139, United States., McCarthy E; Medicine Design and Inflammation and Immunology Research, Pfizer, Cambridge, Massachusetts 02139, United States., Messing D; Medicine Design and Inflammation and Immunology Research, Pfizer, Cambridge, Massachusetts 02139, United States., Miyashiro JS; Medicine Design and Inflammation and Immunology Research, Pfizer, Cambridge, Massachusetts 02139, United States., Mohan S; Medicine Design and Inflammation and Immunology Research, Pfizer, Cambridge, Massachusetts 02139, United States., O'Connell TN; Medicine Design, Pfizer, Groton, Connecticut 06340, United States., Ohren JF; Medicine Design, Pfizer, Groton, Connecticut 06340, United States., Parikh MD; Medicine Design, Pfizer, Groton, Connecticut 06340, United States., Schmidt M; Medicinal Chemistry and Inflammation and Immunology Research, Pfizer, St. Louis, Missouri 63017, United States., Selness SR; Medicinal Chemistry and Inflammation and Immunology Research, Pfizer, St. Louis, Missouri 63017, United States., Springer JR; Medicine Design and Inflammation and Immunology Research, Pfizer, Cambridge, Massachusetts 02139, United States., Thanabal V; Medicine Design, Pfizer, Groton, Connecticut 06340, United States., Trujillo JI; Medicine Design, Pfizer, Groton, Connecticut 06340, United States., Walker DP; Medicinal Chemistry and Inflammation and Immunology Research, Pfizer, St. Louis, Missouri 63017, United States., Wan ZK; Medicine Design and Inflammation and Immunology Research, Pfizer, Cambridge, Massachusetts 02139, United States., Withka JM; Medicine Design, Pfizer, Groton, Connecticut 06340, United States., Wittwer AJ; Medicinal Chemistry and Inflammation and Immunology Research, Pfizer, St. Louis, Missouri 63017, United States., Wood NL; Medicine Design and Inflammation and Immunology Research, Pfizer, Cambridge, Massachusetts 02139, United States., Xing L; Medicine Design and Inflammation and Immunology Research, Pfizer, Cambridge, Massachusetts 02139, United States., Zapf CW; Medicine Design and Inflammation and Immunology Research, Pfizer, Cambridge, Massachusetts 02139, United States., Douhan J 3rd; Medicine Design and Inflammation and Immunology Research, Pfizer, Cambridge, Massachusetts 02139, United States.
Jazyk:	angličtina
Zdroj:	ACS medicinal chemistry letters [ACS Med Chem Lett] 2018 Dec 03; Vol. 10 (1), pp. 80-85. Date of Electronic Publication: 2018 Dec 03 (Print Publication: 2019).
DOI:	10.1021/acsmedchemlett.8b00461
Abstrakt:	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. Competing Interests: The authors declare no competing financial interest.
Databáze:	MEDLINE
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