Synthesis and structure-affinity relationships of 4-(5-Aryl-1,2,3,6-tetrahydropyridino)pyrimidine derivatives as corticotropin-releasing factor1 receptor antagonists

Article abstract of DOI:10.1016/S0968-0896(01)00004-9

Recently, various non-peptide corticotropin-releasing factor₁ (CRF₁) receptor antagonists have been reported. Structure-affinity relationships (SARs) of non-peptide CRF₁ 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). We previously presented 4-aryl-1,2,3,6-tetrahydropyridinopyrimidine derivatives including potent CRF receptor ligands 1a and 1b and proposed that the 4-aryl-1,2,3,6-tetrahydropyridino moiety might be useful as a substituent in the Up-Area. Our interest shifted to 5-aryl-1,2,3,6-tetrahydropyridinopyrimidine derivatives 2, among which compound 2m (CRA0165) had highest affinity for CRF₁ receptors (IC₅₀=11 nM). We report here the design, synthesis and SARs of derivatives 2.