title: 5-(Tryptophyl)amino-1,3-dioxoperhydropyrido[1,2-c]pyrimidine-based potent and selective CCK(1) receptor antagonists: structure-activity relationship studies on the central 1,3-dioxoperhydropyrido[1,2-c]pyrimidine scaffold.
abstract: To further define the pharmacophore of the potent and selective 5-(tryptophyl)amino-1,3-dioxoperhydropyrido[1,2-c]pyrimidine-based CCK(1) receptor antagonists the electronic and topographic properties of the central 1,3-dioxoperhydro-pyrido[1,2-c]pyrimidine scaffold have been modified. With this aim, the 1- and 3-oxo groups have been replaced by the thioxo- and deoxi-analogues, and the fused piperidine ring has been contracted to the corresponding pyrrolidine moiety. The results of the evaluation of the new analogues as CCK receptor ligands, in rat pancreas and cerebral cortex preparations, showed that, whereas replacement of oxygen with sulfur is allowed, reduction of the 1- or 3-oxo groups or the contraction of the fused piperidine ring lead to the complete loss of binding affinity at CCK(1) receptors. The thioxo-analogues 5a, 8a, 12a, and 12b showed functional CCK(1) antagonist activity, inhibiting the CCK-8-stimulated amylase release from pancreatic acinar cells. The 1-thioxo analogue 5a, with subnanomolar affinity (IC(50) = 0.09 x 10(-9) M), was found to be the most potent and selective compound within the family of 5-(tryptophyl)amino-1,3-dioxoperhydropyrido[1,2-c]pyrimidine-based CCK(1) antagonists.
authors.affiliation: Instituto de Química Médica (CSIC), Juan de la Cierva 3, E-28006 Madrid, Spain.
authors.forename: J M
authors.initials: JM
authors.lastname: Bartolomé-Nebreda
authors.forename: M T
authors.initials: MT
authors.lastname: García-López
authors.forename: R
authors.initials: R
authors.lastname: González-Muñiz
authors.forename: E
authors.initials: E
authors.lastname: Cenarruzabeitia
authors.forename: M
authors.initials: M
authors.lastname: Latorre
authors.forename: J
authors.initials: J
authors.lastname: Del Río
authors.forename: R
authors.initials: R
authors.lastname: Herranz
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D066298:In Vitro Techniques; D010179:Pancreas / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D043886:Receptor, Cholecystokinin A; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C440618:2-benzyl-5-(N-(tert-butoxycarbonyl)tryptophyl)amino-3-oxo-1-thioxoperhydropyrido(1,2-c)pyrimidine; D011743:Pyrimidines; D011744:Pyrimidinones; D043886:Receptor, Cholecystokinin A; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; D014364:Tryptophan