Synthesis and Stereochemical Structure−Activity Relationships of 1,3-Dioxoperhydropyrido[1,2-c]pyrimidine Derivatives:  Potent and Selective Cholecystokinin-A Receptor Antagonists

Abstract

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.

Cholecystokinin antagonists: Pharmacological and therapeutic potential

“…Particularly, the use of the 1,3-dioxoperhydropyrido[1,2-c]pyrimidine scaffold led to the discovery of a family of highly potent and selective CCK 1 receptor antagonists. 238 The prototype of this group of antagonists IQM-95,333 (95) showed nanomolar CCK 1 affinity, comparable to that shown by devazepide (18) in the same assay, but with a higher selectivity, as it was devoid of affinity at brain CCK 2 receptors at the highest concentration assayed (10 À5 M). This compound inhibited the CCK-8-stimulated amylase release from rat pancreatic acini with similar potency (IC 50 ¼ 21.3 nM) to that of devazepide (IC 50 ¼ 25.4 nM).…”

“…This study showed the importance of the (4aS,5R)-stereochemistry at the 1,3-dioxoperhydropyrido[1,2-c]-pyrimidine template (compare compounds 95-98, Table XIV) and the L-configuration at the tryptophan residue as essential requirements for CCK 1 binding affinity and subtype receptor selectivity. 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.…”

Twenty years of non-peptide CCK1receptor antagonists: all that glitters is not gold

“…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].…”

“…The first bicyclic system used as a spacer between Trp 30 and Phe 33 of CCK 4 was the 3-oxoindolizidine skeleton, thus obtaining compounds endowed with micromolar affinity at CCK 1 -R or CCK 2 -R depending on the stereochemistry [75]. Replacing the 3-oxoindolizidine skeleton by the rigid analogue framework of the 1,3-dioxoperhydropyrido[1,2-c]pyrimidine led to the discovery of a class of highly potent and selective CCK 1 -R antagonists [76]. The success of this new scaffold has been attributed to its capacity to impart a more appropriate spatial orientation to the aromatic side chains at the receptor recognition site.…”

“…The success of this new scaffold has been attributed to its capacity to impart a more appropriate spatial orientation to the aromatic side chains at the receptor recognition site. The prototype of this group of antagonists IQM-95,333 (36, Figure 8) [229] showed nanomolar CCK 1 -R affinity (K i = 0.6 nM, Table 4), comparable to that shown by devazepide in the same assay, but with a higher selectivity (> 8000) as it was devoid of affinity at brain CCK 2 -R at the highest concentration assayed (10 µM) [76]. This compound inhibited the CCK-stimulated amylase release from rat pancreatic acini with similar potency (IC 50 = 21.3 nM) to that of devazepide (IC 50 = 25.4 nM) [77].…”