title: 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.
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.
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: D000345:Affinity Labels; D000818:Animals; D015195:Drug Design; D005625:Frontal Lobe / Q000378:metabolism; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D009206:Myocardium / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D011687:Purines / Q000138:chemical synthesis* / Q000494:pharmacology*; 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: D000345:Affinity Labels; D011687:Purines; D011743:Pyrimidines; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1