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 substituent at N2-position.
abstract: To establish structure-activity relationships a new series of analogues of the highly potent and selective CCK(1) receptor antagonist (4aS,5R)-2-benzyl-5-(N-Boc-tryptophyl)amino-1,3-dioxoperhydropyrido[1,2-c]-pyrimidine (1a) modified at N2-position of the central scaffold has been prepared and evaluated as CCK receptor ligands. With this aim the N2-benzyl group has been replaced by methyl, cyclohexyl, aromatic groups, 1-phenylethyl, and 1-carboxy-2-phenylethyl group. Then, substituents with different electronic and steric properties were introduced into different positions of the phenyl group of analogues 19a and 19b. The results of the CCK receptor binding and in vitro functional activity evaluation suggest the importance of the lipophilic character and an appropriate spatial orientation of the moiety linked at the N2-position of the 1,3-dioxoperhydropyrido[1,2-c]pyrimidine template for potent and selective binding and antagonist activity at CCK(1) receptor subtype. The 2-cyclohexyl and (2S)-1-naphthyl derivatives 18a and (2S)-20a have emerged as more potent and selective CCK(1) receptor antagonists than the lead compound 1a. Additionally, the results confirm the (4aS,5R)-stereochemistry at the central bicyclic skeleton as an essential structural requirement for potent binding to this receptor subtype.
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: R
authors.initials: R
authors.lastname: Patiño-Molina
authors.forename: M
authors.initials: M
authors.lastname: Martín-Martínez
authors.forename: I
authors.initials: I
authors.lastname: Gómez-Monterrey
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: D000681:Amylases / Q000378:metabolism; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D010179:Pancreas / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014364:Tryptophan / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D008024:Ligands; D011743:Pyrimidines; D011949:Receptors, Cholecystokinin; D014364:Tryptophan; D000681:Amylases