5-(Tryptophyl)amino-1,3-dioxoperhydropyrido[1,2-c]pyrimidine-based potent and selective CCK1 receptor antagonists:: Structural modifications at the tryptophan domain

被引:12
作者
Bartolomé-Nebreda, JM
Gómez-Monterrey, I
García-López, MT
González-Muñiz, R
Martín-Martínez, M
Ballaz, S
Cenarruzabeitia, E
LaTorre, M
Del Río, J
Herranz, R
机构
[1] CSIC, Inst Quim Med, E-28006 Madrid, Spain
[2] Univ Navarra, Dept Farmacol, E-31080 Pamplona, Spain
关键词
D O I
10.1021/jm991078x
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Analogues of the previously reported potent and highly selective CCK1 receptor antagonist (4aS,5R)-2-benzyl-5-(N-Boc-tryptophyl)amino-1,3-dioxoperhyropyrido-[1,2-c]pyrimidine (2a) were prepared to explore the structural requirements at the Boc-tryptophan domain for CCK1 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 highly strict structural requirements: the type and orientation of the Trp side chain, the H-bonding acceptor carbonyl group of the carboxamide bond, and the presence of the Trp amino protection Boc. Replacement of this acid-labile group with 3,3-dimethylbutyryl or tert-butylaminocarbonyl conferred acid stability to analogues 14a and 15a, which retained a high potency and selectivity in binding to CCK1 receptors, as well as an in vivo antagonist activity against the acute pancreatitis induced by caerulein in rats. Oral administration of compounds 14a and 15a also produced a lasting antagonism to the hypomotility induced by CCK-8 in mice, suggesting a good bioavailability and metabolic stability.
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页码:4659 / 4668
页数:10
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