Discovery of a novel series of pyridine and pyrimidine carboxamides as potent and selective covalent inhibitors of Btk

Bioorg Med Chem Lett. 2018 Nov 15;28(21):3419-3424. doi: 10.1016/j.bmcl.2018.09.033. Epub 2018 Sep 27.

Abstract

Btk is an attractive target for the treatment of a range of Bcell malignancies as well as several autoimmune diseases such as murine lupus and rheumatoid arthritis. Several covalent irreversible inhibitors of Btk are currently in development including ibrutinib which was approved for treatment of B-cell malignancies. Herein, we describe our efforts using X-ray guided structure based design (SBD) to identify a novel chemical series of covalent Btk inhibitors. The resulting pyridine carboxamides were potent and selective inhibitors of Btk having excellent enzymatic and cellular inhibitory activity.

Keywords: Btk inhibitor; Covalent; Fragment; Irreversible.

MeSH terms

  • Adenine / analogs & derivatives
  • Administration, Oral
  • Agammaglobulinaemia Tyrosine Kinase / antagonists & inhibitors*
  • Animals
  • Caco-2 Cells
  • Humans
  • Mice
  • Molecular Structure
  • Piperidines
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrazoles / pharmacology
  • Pyridines / administration & dosage
  • Pyridines / chemical synthesis
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Pyrimidines / administration & dosage
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Piperidines
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyridines
  • Pyrimidines
  • ibrutinib
  • Agammaglobulinaemia Tyrosine Kinase
  • BTK protein, human
  • Adenine