Chemical modification of aryl-1,2,3,6-tetrahydropyridinopyrimidine derivative to discover corticotropin-releasing factor(1) receptor antagonists: aryl-1,2,3,6-tetrahydropyridino-purine, -3H-1,2,3-triazolo[4,5-d)pyrimidine, -purin-8-one, and -7H-pyrrolo[2,3-d]pyrimidine derivatives

Bioorg Med Chem. 2001 May;9(5):1357-63. doi: 10.1016/s0968-0896(01)00005-0.

Abstract

Structure-affinity relationships (SARs) of non-peptide CRF(1) antagonists suggest that such antagonists can be constructed of three units: a hydrophobic unit (Up-Area), a proton accepting unit (Central-Area), and an aromatic unit (Down-Area). Recently, various non-peptide corticotropin-releasing factor(1) (CRF(1)) receptor antagonists obtained by modification of the Central-Area have been reported. In contrast, we modified the Up-Area and presented 4- or 5-aryl-1,2,3,6-tetrahydropyridinopyrimidine derivatives including potent CRF receptor ligands 1a-c, and proposed that the 4- or 5-aryl-1,2,3,6-tetrahydropyridino moiety might be useful as a substituent in the Up-Area. Our interest shifted to the chemical modification in which the pyrimidine ring of 1a-c was replaced by other heterocycles, purine ring of 2, 3H-1,2,3-triazolo[4,5-d]pyrimidine ring of 3, purin-8-one ring of 4 and 7H-pyrrolo[2,3-d]pyrimidine ring of 5. Among them, 5-aryl-1,2,3,6-tetrahydropyridinopurine compound 6j (CRA0186) had the highest affinity for CRF(1) receptors (IC(50)=20nM). We report here the synthesis and SARs of derivatives 6-9.

MeSH terms

  • Affinity Labels
  • Animals
  • Drug Design
  • Frontal Lobe / metabolism
  • In Vitro Techniques
  • Inhibitory Concentration 50
  • Myocardium / metabolism
  • Protein Binding / physiology
  • Purines / chemical synthesis*
  • Purines / pharmacology*
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / pharmacology*
  • Rats
  • Receptors, Corticotropin-Releasing Hormone / antagonists & inhibitors*
  • Receptors, Corticotropin-Releasing Hormone / metabolism
  • Structure-Activity Relationship

Substances

  • Affinity Labels
  • Purines
  • Pyrimidines
  • Receptors, Corticotropin-Releasing Hormone
  • CRF receptor type 1