Discovery of aminoquinazolines as potent, orally bioavailable inhibitors of Lck: synthesis, SAR, and in vivo anti-inflammatory activity

J Med Chem. 2006 Sep 21;49(19):5671-86. doi: 10.1021/jm0605482.

Abstract

The lymphocyte-specific kinase (Lck) is a cytoplasmic tyrosine kinase of the Src family expressed in T cells and natural killer (NK) cells. Genetic evidence in both mice and humans demonstrates that Lck kinase activity is critical for signaling mediated by the T cell receptor (TCR), which leads to normal T cell development and activation. Selective inhibition of Lck is expected to offer a new therapy for the treatment of T-cell-mediated autoimmune and inflammatory disease. Screening of our kinase-preferred collection identified aminoquinazoline 1 as a potent, nonselective inhibitor of Lck and T cell proliferation. In this report, we describe the synthesis and structure-activity relationships of a series of novel aminoquinazolines possessing in vitro mechanism-based potency. Optimized, orally bioavailable compounds 32 and 47 exhibit anti-inflammatory activity (ED(50) of 22 and 11 mg/kg, respectively) in the anti-CD3-induced production of interleukin-2 (IL-2) in mice.

MeSH terms

  • Administration, Oral
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Benzamides / chemical synthesis*
  • Benzamides / chemistry
  • Benzamides / pharmacology
  • Biological Availability
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Female
  • Humans
  • In Vitro Techniques
  • Interleukin-2 / biosynthesis
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / antagonists & inhibitors*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Models, Molecular
  • Quinazolines / chemical synthesis*
  • Quinazolines / chemistry
  • Quinazolines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship
  • T-Lymphocytes / cytology
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • Tumor Necrosis Factor-alpha / biosynthesis

Substances

  • 4-methyl-3-(2-(2-morpholinoethylamino)quinazolin-6-yl)-N-(3-(trifluoromethyl)phenyl)benzamide
  • 4-methyl-3-(2-(methylamino)quinazolin-6-yl)-N-(2-(1-methylpiperidin-4-yloxy)-5-(trifluoromethyl)phenyl)benzamide
  • Anti-Inflammatory Agents, Non-Steroidal
  • Benzamides
  • Interleukin-2
  • Quinazolines
  • Tumor Necrosis Factor-alpha
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck)