The discovery of orally active triaminotriazine aniline amides as inhibitors of p38 MAP kinase

J Med Chem. 2004 Dec 2;47(25):6283-91. doi: 10.1021/jm049521d.

Abstract

A new structural class of triaminotriazine aniline amides possessing potent p38 enzyme activity has been discovered. The initial hit (compound 1a) was identified through screening the Pharmacopeia ECLiPS compound collection. SAR modification led to the identification of a short acting triaminotriazine aniline methoxyamide (compound 1m) possessing in vitro and in vivo oral activity in animal models of acute and chronic inflammatory disease. An X-ray crystal structure of compound 1m in this class, cocrystallized with unactivated p38 alpha protein, indicates that these compounds bind to the ATP binding pocket and possess key H-bonding interactions within a deeper cleft. Hydrogen bonding between one of the triazine nitrogens and the backbone NH of the Met109 residue occurs through a water molecule. The methoxyamide NH and carbonyl oxygen are within H-bonding distance of Glu71 and Asp168.

MeSH terms

  • Administration, Oral
  • Amides / chemical synthesis*
  • Amides / chemistry
  • Amides / pharmacology
  • Aniline Compounds / chemical synthesis*
  • Aniline Compounds / chemistry
  • Aniline Compounds / pharmacology
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Arthritis, Experimental / drug therapy
  • Arthritis, Experimental / pathology
  • Benzamides / chemical synthesis*
  • Benzamides / chemistry
  • Benzamides / pharmacology
  • Crystallography, X-Ray
  • Female
  • Humans
  • In Vitro Techniques
  • Mice
  • Mice, Inbred BALB C
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism
  • Models, Molecular
  • Molecular Structure
  • Monocytes / drug effects
  • Monocytes / metabolism
  • Rats
  • Rats, Inbred Lew
  • Structure-Activity Relationship
  • Triazines / chemical synthesis*
  • Triazines / chemistry
  • Triazines / pharmacology
  • Tumor Necrosis Factor-alpha / biosynthesis
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • p38 Mitogen-Activated Protein Kinases / chemistry

Substances

  • Amides
  • Aniline Compounds
  • Anti-Inflammatory Agents, Non-Steroidal
  • Benzamides
  • N-methoxy-4-methyl-3-(4-(methyl(neopentyl)amino)-6-(4-methyl-1,4-diazepan-1-yl)-1,3,5-triazin-2-ylamino)benzamide
  • Triazines
  • Tumor Necrosis Factor-alpha
  • p38 Mitogen-Activated Protein Kinases