5-(Tryptophyl)amino-1,3-dioxoperhidropyrido[1,2-c]pyrimidine-based potent and selective CCK1 receptor antagonists: Structure-activity relationship studies on the substituents at N2-position
| Autor: | M. T. Garcia‐Lopez, Miriam Latorre, Rosario Herranz, I. Gomez‐Monterrey, del Río J, Rosario Patiño-Molina, Rosario González-Muñiz, J M Bartolomé-Nebreda, Edurne Cenarruzabeitia, Mercedes Martín-Martínez |
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| Přispěvatelé: | J. M., BARTOLOME NEBREDA, R., PATINO MOLINA, M., MARTIN MARTINEZ, GOMEZ MONTERREY, ISABEL MARIA, M. T., GARCIA LOPEZ, R., GONZALEZ MUNIZ, E., Cenarruzabeitia, M., LA TORRE, J., DEL RIO, R. H. E. R. R. A. N., Z. |
| Jazyk: | angličtina |
| Rok vydání: | 2001 |
| Předmět: |
Magnetic Resonance Spectroscopy
Pyrimidine medicine.drug_class Stereochemistry In Vitro Techniques Ligands Cholecystokinin receptor chemistry.chemical_compound Structure-Activity Relationship Drug Discovery medicine Moiety Structure–activity relationship Animals Receptor Pancreas Brain Chemistry Cerebral Cortex Bicyclic molecule Chemistry Antagonist Tryptophan Receptor antagonist Rats Pyrimidines Amylases Molecular Medicine Receptors Cholecystokinin |
| Popis: | 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 With this aim the N2-benzyl group has been replaced by methyl, cyclohexyl, aromatic groups, 1-phenylethyl, and 1-carboxy-2-phenylethyl group.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. |
| Databáze: | OpenAIRE |
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