Structure-based drug design of RN486, a potent and selective Bruton's tyrosine kinase (BTK) inhibitor, for the treatment of rheumatoid arthritis

J Med Chem. 2015 Jan 8;58(1):512-6. doi: 10.1021/jm500305p. Epub 2014 Apr 16.

Abstract

Structure-based drug design was used to guide the optimization of a series of selective BTK inhibitors as potential treatments for Rheumatoid arthritis. Highlights include the introduction of a benzyl alcohol group and a fluorine substitution, each of which resulted in over 10-fold increase in activity. Concurrent optimization of drug-like properties led to compound 1 (RN486) ( J. Pharmacol. Exp. Ther. 2012 , 341 , 90 ), which was selected for advanced preclinical characterization based on its favorable properties.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Agammaglobulinaemia Tyrosine Kinase
  • Arthritis, Rheumatoid / drug therapy*
  • Crystallography, X-Ray
  • Drug Design
  • Humans
  • Isoquinolines / chemistry
  • Isoquinolines / metabolism
  • Isoquinolines / pharmacology*
  • Models, Chemical
  • Models, Molecular
  • Molecular Structure
  • Protein Binding
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / chemistry
  • Protein-Tyrosine Kinases / metabolism

Substances

  • Isoquinolines
  • RN486
  • Protein-Tyrosine Kinases
  • Agammaglobulinaemia Tyrosine Kinase
  • BTK protein, human