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
  • 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.

Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-164002
    PF-303
    BTK Inhibitor
    target: Btk
    Research Areas: Others