title: Synthesis and structure-affinity relationships of 4-(5-Aryl-1,2,3,6-tetrahydropyridino)pyrimidine derivatives as corticotropin-releasing factor(1) receptor antagonists.
abstract: Recently, various non-peptide corticotropin-releasing factor(1) (CRF(1)) receptor antagonists have been reported. 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). 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 CRF(1) receptors (IC(50)=11nM). We report here the design, synthesis and SARs of derivatives 2.
authors.affiliation: 1st Laboratory, Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Ohmiya, Saitama 330-8530, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kumagai
authors.forename: T
authors.initials: T
authors.lastname: Okubo
authors.forename: H
authors.initials: H
authors.lastname: Kataoka-Okubo
authors.forename: S
authors.initials: S
authors.lastname: Chaki
authors.forename: S
authors.initials: S
authors.lastname: Okuyama
authors.forename: A
authors.initials: A
authors.lastname: Nakazato
mesh_terms: D000818:Animals; D015195:Drug Design; D005625:Frontal Lobe / Q000378:metabolism; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D008024:Ligands; D008968:Molecular Conformation; D015394:Molecular Structure; D009206:Myocardium / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011725:Pyridines / Q000138:chemical synthesis; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D000099052:CRF Receptor, Type 1
chemical_list: C434335:4-(5-aryl-1,2,3,6-tetrahydropyridino)pyrimidine; D008024:Ligands; D011725:Pyridines; D011743:Pyrimidines; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1