Synthesis and stereochemical structure-activity relationships of 1,3-dioxoperhydropyrido[1,2-c]pyrimidine derivatives: potent and selective cholecystokinin-A receptor antagonists.
The synthesis and stereochemical structure--activity relationships of a new class of potent and selective non-peptide cholecystokinin-A (CCK-A) receptor antagonists based on the 1,3-dioxoperhydropyrido[1,2-c]pyrimidine skeleton are described. The most potent member of this series of eight diastereoisomers, (4aS,5R)-2-benzyl-5-[N-[(tert-butoxycarbonyl)-L-tryptophyl]-amino] - 1,3-dioxoperhydropyrido[1,2-c]pyrimidine, displays nanomolar CCK-A receptor affinity and higher than 8000-fold potency at the CCK-A than at the CCK-B receptor. As CCK-A antagonist, this compound inhibits the CCK-8-evoked amylase release from pancreatic acinar cells at a low concentration, similar to that of the typical antagonist Devazepide. Highly strict stereochemical requirements for CCK-A receptor binding and selectivity have been found. The L-Trp and the 4a,5-trans disposition of the bicyclic perhydropyrido[1,2-c]pyrimidine are essential for binding potency and selectivity.
Martín-Martínez
M
M
Instituto de Química Médica (CSIC), Madrid, Spain.
Bartolomé-Nebreda
J M
JM
Gómez-Monterrey
I
I
González-Muñiz
R
R
García-López
M T
MT
Ballaz
S
S
Barber
A
A
Fortuño
A
A
Del Río
J
J
Herranz
R
R
D000681:Amylases / Q000378:metabolism; D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology; D001921:Brain / Q000187:drug effects; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020109:Devazepide; D008968:Molecular Conformation; D015394:Molecular Structure; D010179:Pancreas / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D043886:Receptor, Cholecystokinin A; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012844:Sincalide / Q000494:pharmacology; D013329:Structure-Activity Relationship
D001570:Benzodiazepinones; D002219:Carbamates; C108038:IQM 95333; D011743:Pyrimidines; D011744:Pyrimidinones; D043886:Receptor, Cholecystokinin A; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; D000681:Amylases; D020109:Devazepide; D012844:Sincalide