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

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.
Mark E Schnute 1,  Stephen E Benoit 1,  Ingrid P Buchler 1,  Nicole Caspers 2,  Margaret L Grapperhaus 3,  Seungil Han 2,  Rajeev Hotchandani 1,  Nelson Huang 1,  Robert O Hughes 1,  Brian M Juba 1,  Kyung-Hee Kim 1,  Erica Liu 1,  Erin McCarthy 1,  Dean Messing 1,  Joy S Miyashiro 1,  Shashi Mohan 1,  Thomas N O'Connell 2,  Jeffrey F Ohren 2,  Mihir D Parikh 2,  Michelle Schmidt 3,  Shaun R Selness 3,  John R Springer 1,  Venkataraman Thanabal 2,  John I Trujillo 2,  Daniel P Walker 3,  Zhao-Kui Wan 1,  Jane M Withka 2,  Arthur J Wittwer 3,  Nancy L Wood 1,  Li Xing 1,  Christoph W Zapf 1,  John Douhan 3rd 1
Affiliations

Affiliations

  • 1 Medicine Design and Inflammation and Immunology Research, Pfizer, Cambridge, Massachusetts 02139, United States.
  • 2 Medicine Design, Pfizer, Groton, Connecticut 06340, United States.
  • 3 Medicinal Chemistry and Inflammation and Immunology Research, Pfizer, St. Louis, Missouri 63017, United States.
PMID: 30655951 DOI: 10.1021/acsmedchemlett.8b00461
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-164002
    BTK抑制剂
    Btk
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