5-(Tryptophyl)amino-1,3-dioxoperhydropyrido[1,2-c]pyrimidine-based potent and selective CCK(1) receptor antagonists: structural modifications at the tryptophan domain.
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 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 CCK(1) 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.
Bartolomé-Nebreda
J M
JM
Insituto de Química Médica (CSIC), Juan de la Cierva 3, E-28006 Madrid, Spain.
Gómez-Monterrey
I
I
García-López
M T
MT
González-Muñiz
R
R
Martín-Martínez
M
M
Ballaz
S
S
Cenarruzabeitia
E
E
LaTorre
M
M
Del Río
J
J
Herranz
R
R
D000208:Acute Disease; D000284:Administration, Oral; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D002108:Ceruletide; D006948:Hyperkinesis / Q000139:chemically induced / Q000188:drug therapy; D066298:In Vitro Techniques; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D010179:Pancreas / Q000378:metabolism; D010195:Pancreatitis / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012844:Sincalide; D013329:Structure-Activity Relationship; D014364:Tryptophan / Q000737:chemistry*
C401387:2-benzyl-5-(2-N-(2,2-dimethylpropylcarbonyl)amino-3-(indol-3-yl)propyl)amino-1,3-dioxoperhydropyrido(1,2-c)pyrimidine; C401388:2-benzyl-5-(2-N-(tert-butylaminocarbonyl)amino-3-(indol-3-yl)propyl)amino-1,3-dioxoperhydropyrido(1,2-c)pyrimidine; D011725:Pyridines; D011744:Pyrimidinones; D011949:Receptors, Cholecystokinin; D002108:Ceruletide; D014364:Tryptophan; D012844:Sincalide