Title: Aminopyrazole Carboxamide Bruton’s Tyrosine Kinase Inhibitors. Irreversible to Reversible Covalent Reactive Group Tuning

Journal Article · · ACS Medicinal Chemistry Letters
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  1. Pfizer, Cambridge, MA (United States)
  2. Pfizer, Groton, CT (United States)
  3. Pfizer, St. Louis, MO (United States)
+ Show Author Affiliations

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

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE
OSTI ID:
1557277
Journal Information:
ACS Medicinal Chemistry Letters, Journal Name: ACS Medicinal Chemistry Letters Journal Issue: 1 Vol. 10; ISSN 1948-5875
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH

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Cited By (1)

Covalent Small Molecules as Enabling Platforms for Drug Discovery journal February 2020

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