Derivados de 1,3-dioxoperhidropirido[1,2-c]pirimidinas como antagonistas de colecistoquinina

Referencia OEPM: P9501857.-- Fecha de solicitud: 26/09/1995.-- Titulares: Consejo Superior de Investigaciones Científicas (CSIC), Universidad de Navarra.Derivados de 1,3-dioxoperhidropirido[1,2-c]pirimidinas como antagonistas de colecistoquinina (ver figura en archivo de texto adjunto). La presente invención se refiere a derivados de 1,3- dioxoperhidropirido [1,2,-c] piriminas, e intermedios para su preparación de fórmula general (I). Dichos derivados son útiles como antagonistas de colecistoquinina (CCK) y por lo tanto como agentes activos sobre el sistema nervioso central y el periférico.Peer reviewe

CCK-4 restricted analogues containing a 3-oxoindolizidine skeleton

A series of CCK-4 restricted analogues, incorporating a 3-oxoindolizidine bicyclic lactam as conformational constraint, is described. The 8-(Boc-tryptophyl)amino-2-benzyl derivatives behave as weak CCK-A or CCK-B receptor antagonists. The main factors for selectivity are the configuration at C-2 position of the 3-oxoindolizidine ring and at the Trp residue.We thank the Comisión Interministerial de Ciencia y Tecnología (SAF 94 0705) and the Dirección General de Investigaciín Cientffica y Técnica (UE 95-0021) for financial support

Pseudopeptide CCK-4 analogues incorporating the Ψ[CH(CN)NH] peptide bond surrogate

The synthesis, binding to CCK receptors, and in vitro functional activity of pseudopeptide CCK-4 analogues incorporating the (R) or (S) Ψ[CH(CN)NH] peptide bond surrogate at the NIe31-Asp32or or Trp30-NIe13 bonds are described. Z-TrpΨ[(S)CH(CN)NH]NIe-Asp-Phe-NH2 retained the high CCK-B receptor binding affinity of Boc-[NIe31]-CCK-4, and was a potent and selective CCK-B antagonist in the isolated guinea pig ileum. Pseudopeptide CCK-4 analogues incorporating the Ψ[CH(CN)NH] peptide bond surrogate were synthesized and evaluated as CCK receptor ligands. Pseudotetrapeptide (S)-11a retained the high CCK-B receptor binding affinity of Boc-[Nle31]-CCK-4, and was a potent and selective CCK-B antagonist in the isolated guinea pig ileum.We thank the Comisión Interministerial de Ciencia y Tecnología (SAF 94 -0705) and the Dirección General de Investigación Científica y Técnica (UE 95-002 1) for financial support

Pharmacological evaluation of IQM-95,333, a highly selective CCK(A) receptor antagonist with anxiolytic-like activity in animal models

1. The pyridopyrimidine derivative IQM-95,333 ((4aS,5R)-2-benzyl-5-[N(α)-tert-butoxicarbonyl)L-tryptophyl]amino -1,3dioxoperhydropyridol[1,2-c]pyrimidine), a new non-peptide antagonist of cholecystokinin type A (CCK(A)) receptors, has been evaluated in vitro and in vivo in comparison with typical CCK(A) and CCK(B) receptor antagonists, such as devazepide, lorglumide, L-365,260 and PD-135,158. 2. IQM-95,333 displaced [3H]-CCK-8S binding to CCK(A) receptors from rat pancreas with a high potency in the nanomolar range. Conversely, the affinity of this new compound at brain CCK(B) receptors was negligible (IC50 > 10 μM). IQM-95,333 was a more selective CCK(A) receptor ligand than devazepide and other CCK(A) receptor antagonists. 3. Like devazepide, IQM-95,333 was a more potent antagonist of CCK-8S- than of CCK-4-induced contraction of the longitudinal muscle from guinea-pig ileum, suggesting selective antagonism at CCK(A) receptors. 4. IQM-95,333 and devazepide were also potent inhibitors of CCK-8S-stimulated amylase release from isolated pancreatic acini, a CCK(A) receptor-mediated effect. The drug concentrations required (IC50s around 20 nM) were higher than in binding studies to pancreas homogenates. 5. Low doses (50-100 μg kg-1, i.p.) of IQM-95,333 and devazepide, without any intrinsic effect on food intake or locomotion, blocked the hypophagia and the hypolocomotion induced by systemic administration of CCK-8S, two effects associated with stimulation of peripheral CCK(A) receptors. 6. IQM-95,333 showed an anxiolytic-like profile in the light/dark exploration test in mice over a wide dose range (10-5,000 μg kg-1). Typical CCK(A) and CCK(B) antagonists, devazepide and L-365,260 respectively, were only effective within a more limited dose range. 7. In a classical conflict paradigm for the study of anxiolytic drugs, the punished-drinking test, IQM-95,333, devazepide and L-365,260 were effective within a narrow dose range. The dose-response curve for the three drugs was biphasic, suggesting that other mechanisms are operative at higher doses. 8. In conclusion, IQM-95,333 is a potent and selective CCK(A) receptor antagonist both in vitro and in vivo with an anxiolytic-like activity in two different animal models, which can only be attributed to blockade of this CCK receptor subtype.Supported by CICYT (SAF94–0705). We thank Gobierno de Navarra for a fellowship to one of us (S.B.)

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.This work has been supportedby the CICYT (SAF 94-0705) and Comunidad de Madrid(AE 0004/95)