5-Cyanopyrimidine derivatives as a novel class of potent, selective, and orally active inhibitors of p38alpha MAP kinase

J Med Chem. 2005 Oct 6;48(20):6261-70. doi: 10.1021/jm0503594.

Abstract

A novel class of 5-cyanopyrimidine-based inhibitors of p38alpha MAP kinase has been investigated. Analogues optimized through SAR iterations display low nanomolar enzymatic and cellular activity. The in vivo efficacy of this class of p38 inhibitors was demonstrated by 3a and 3b (>50% reduction in TNF levels when orally dosed at 5 mg/kg, 5 h prior to LPS administration in an acute murine model of inflammation). For 3a and 3b, the previously identified N-methoxybenzamide moiety (1) was replaced with N-(isoxazol-3-yl)benzamide, thereby providing increased metabolic stability. Cyanopyrimidine 3a demonstrated 100% oral bioavailability in mouse. High p38 kinase selectivity versus over 20 kinases was observed for analogue 3b. Direct hydrogen bonding of the cyano nitrogen of the 5-cyanopyrimidine core to the backbone NH of Met109 was confirmed by X-ray crystallographic analysis of 3a bound to p38alpha.

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
  • Cells, Cultured
  • Crystallography, X-Ray
  • Female
  • Humans
  • In Vitro Techniques
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / metabolism
  • Lipopolysaccharides / pharmacology
  • Mice
  • Mice, Inbred BALB C
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism
  • Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase 14 / chemistry
  • Models, Molecular
  • Nitriles / chemical synthesis*
  • Nitriles / chemistry
  • Nitriles / pharmacology
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology
  • Rats
  • Structure-Activity Relationship
  • Tumor Necrosis Factor-alpha / biosynthesis

Substances

  • 3-(5-cyano-6-(cyclopentylamino)pyrimidin-4-ylamino)-N-(isoxazol-3-yl)-4-methylbenzamide
  • 3-(5-cyano-6-(isopropylamino)pyrimidin-4-ylamino)-N-(isoxazol-3-yl)-4-methylbenzamide
  • Anti-Inflammatory Agents, Non-Steroidal
  • Benzamides
  • Lipopolysaccharides
  • Nitriles
  • Pyrimidines
  • Tumor Necrosis Factor-alpha
  • Mitogen-Activated Protein Kinase 14