1999
DOI: 10.1021/jm991078x
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Abstract: Analogues of the previously reported potent and highly selective CCK(1) receptor antagonist (4aS, 5R)-2-benzyl-5-(N-Boc-tryptophyl)amino-1,3-dioxoperhydropyrido-[1, 2-c]pyrimidine (2a) were prepared to explore the structural requirements at the Boc-tryptophan domain for CCK(1) receptor affinity. Structural modifications of 2a involved the Trp side chain, its conformational freedom, the Boc group, and the carboxamide bond. Results of the CCK binding and in vitro functional activity evaluation showed three highl… Show more

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Cited by 11 publications
(22 citation statements)
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“…The oxo group reduction produces important topographic changes due to the transformation of the plane sp 2 hybridization into the tetrahedral sp 3 , and also to a loss in the acceptor hydrogen-bonding properties. In regard to the contraction of the fused piperidine ring to a pyrrolidine one, this structural modification affects the topography of the 1,3-dioxoperhydropyrido[1,2- c ]pyrimidine skeleton, and, therefore, the spatial arrangement of the groups linked to positions 2 and 5, both critical for receptor recognition. , As these important topographic changes could modify the stereochemical requirements for binding at CCK 1 and CCK 2 receptors, the complete stereochemical space defined by the eight stereoisomers at the Trp residue and at positions 4a and 5 of the central skeleton was explored in this case. The present paper deals with the synthesis and CCK receptor binding profile of this new series of derivatives modified at the 1,3-dioxoperhydropyrido[1,2- c ]pyrimidine scaffold.…”
Section: Introductionmentioning
confidence: 99%
“…The oxo group reduction produces important topographic changes due to the transformation of the plane sp 2 hybridization into the tetrahedral sp 3 , and also to a loss in the acceptor hydrogen-bonding properties. In regard to the contraction of the fused piperidine ring to a pyrrolidine one, this structural modification affects the topography of the 1,3-dioxoperhydropyrido[1,2- c ]pyrimidine skeleton, and, therefore, the spatial arrangement of the groups linked to positions 2 and 5, both critical for receptor recognition. , As these important topographic changes could modify the stereochemical requirements for binding at CCK 1 and CCK 2 receptors, the complete stereochemical space defined by the eight stereoisomers at the Trp residue and at positions 4a and 5 of the central skeleton was explored in this case. The present paper deals with the synthesis and CCK receptor binding profile of this new series of derivatives modified at the 1,3-dioxoperhydropyrido[1,2- c ]pyrimidine scaffold.…”
Section: Introductionmentioning
confidence: 99%
“…Moreover, compound 103 by intraperitoneal or oral administration showed protective effect on experimental acute pancreatitis induced by caerulein in rats. 244 Respecting the N2-substituent, the SAR study indicated the importance of its lipophilic character and an appropriate spatial orientation. Thus, the benzyl group at this position in the prototype 95 was replaced by cyclohexyl, phenyl, or naphtyl groups without affecting binding affinity and selectivity, while its replacement by methyl group led to almost the complete loss of the binding affinity.…”
Section: 3-dioxoperhydropyrido[12-c]pyrimidine-based Cck 1 Antamentioning
confidence: 98%
“…238 The presence of the tertbutoxycarbonyl group (Boc) and the amide bond, or an appropriate H-bonding surrogate such as c[CH(CN)NH] (105), were also critical for the binding at CCK 1 receptors, while the replacement of the tryptophan residue by other aromatic amino acids, such as Phe (99) or a-Me-Trp (100) led to more than 10-fold decrease in the binding potency. 244 Interestingly, the replacement of the acid-labile Boc group by their bioisosters tert-butylaminocarbonyl (103) or 3,3-dimethylbutyryl groups conferred acid stability and a longer antagonism of the CCK-8-induced hypomotility in mice by oral administration. Moreover, compound 103 by intraperitoneal or oral administration showed protective effect on experimental acute pancreatitis induced by caerulein in rats.…”
Section: 3-dioxoperhydropyrido[12-c]pyrimidine-based Cck 1 Antamentioning
confidence: 99%
“…This study showed that the (4aS,5R)-stereochemistry at the 1,3-dioxoperhydro-pyrido-[1,2-c]-pyrimidine template and the L-configuration at the Trp residue were essential requirements for CCK 1 -R binding affinity and selectivity [76]. The presence of the tert-butoxycarbonyl group (Boc) and the amide bond were also critical for the CCK 1 -R affinity, whereas the replacement of the Trp residue by other aromatic amino acids (Phe or α-Me-Trp) led to a > 10-fold decrease in the binding potency [78]. Regarding the N2-substituent, the SAR study indicated the importance of its lipophilic character and an appropriate spatial orientation.…”
Section: Conformationally Restricted Peptoidsmentioning
confidence: 99%