RESUMEN
A series of 4-substituted 4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepines was prepared by standard methodology. These compounds were tested in vitro as antagonists of the binding of [125I]cholecystokinin (CCK) to rat pancreas and guinea pig brain receptors and of the binding of [125I]gastrin to guinea pig gastric glands. All compounds proved to have greater affinity for the peripheral CCK receptor with some analogues having IC50's in the subnanomolar range. In vivo activity of selected compounds in mice is presented and the structure/activity profile of this class of benzodiazepines as CCK antagonists is discussed.
Asunto(s)
Benzodiazepinas/síntesis química , Colecistoquinina/antagonistas & inhibidores , Triazoles/síntesis química , Animales , Benzodiazepinas/farmacología , Encéfalo/metabolismo , Colecistoquinina/metabolismo , Vaciamiento Gástrico/efectos de los fármacos , Mucosa Gástrica/metabolismo , Cobayas , Indicadores y Reactivos , Páncreas/metabolismo , Ratas , Receptores de Colecistoquinina/efectos de los fármacos , Receptores de Colecistoquinina/metabolismo , Sincalida/antagonistas & inhibidores , Sincalida/farmacología , Relación Estructura-Actividad , Triazoles/farmacologíaRESUMEN
A series of statine-containing tetrapeptides, systematically modified at the carboxy terminus with various hydrophobic aromatic groups, is described. These compounds were tested in vitro for their ability to inhibit porcine, human plasma, and purified human kidney renins. These analogues help to define optimal binding aspects in a region of the enzyme that appears to be specific for spatial arrangement of aromatic groups. Replacement of the metabolically labile Phe amide with nonpeptidal groups proved possible while achieving inhibitory potency in the nanomolar range vs. porcine kidney renin. For the compounds 6i, 6m, and 6o, a large discrepancy in potency between the human plasma and the purified human kidney renin assays was observed. This disparity does not appear to be a consequence of a previously proposed plasma binding component.
Asunto(s)
Aminoácidos , Inhibidores Enzimáticos/síntesis química , Oligopéptidos/farmacología , Renina/antagonistas & inhibidores , Animales , Inhibidores Enzimáticos/farmacología , Humanos , Concentración de Iones de Hidrógeno , Riñón/enzimología , Relación Estructura-Actividad , PorcinosRESUMEN
3-(Acylamino)-5-phenyl-2H-1,4-benzodiazepines, antagonists of the peptide hormone cholecystokinin (CCK), are described. Developed by reasoned modification of the known anxiolytic benzodiazepines, these compounds provide highly potent, orally effective ligands selective for peripheral (CCK-A) receptors, with binding affinities approaching or equaling that of the natural ligand CCK-8. The distinction between CCK-A receptors on the one hand and CNS (CCK-B), gastrin, and central benzodiazepine receptors on the other is demonstrated by using the structure-activity profiles of the new compounds. Details of the binding of these agents to CCK-A receptors are examined, and the method of development of these compounds is discussed in terms of its relevance to the general problem of drug discovery.
Asunto(s)
Benzodiazepinas/síntesis química , Colecistoquinina/antagonistas & inhibidores , Diseño de Fármacos , Administración Oral , Animales , Benzodiazepinas/metabolismo , Fenómenos Químicos , Química , Ratones , Receptores de Colecistoquinina/metabolismo , Receptores de GABA-A/metabolismo , Relación Estructura-ActividadRESUMEN
Tifluadom, a kappa-opioid agonist and cholecystokinin-A (CCK-A) receptor antagonist, was utilized as a model to prepare a series of 2-(aminomethyl)- and 3-(aminomethyl)-1,4-benzodiazepines. These compounds were tested in vitro as inhibitors of the binding of [125I]CCK to rat pancreas and guinea pig brain receptors. All compounds with IC50's less than 100 microM proved to have greater affinity for the CCK-A receptor, with the most potent analogue, 6e, having an IC50 of 0.16 microM. The benzodiazepines described in this study are simultaneously CCK-A and opioid receptor ligands. The ramification of this dichotomy on current concepts of peptide hormone action are discussed. These results further demonstrate the versatility of the benzodiazepine core structure for designing nonpeptide ligands for peptide receptors and the ability to fine-tune the receptor interactions of these benzodiazepines by appropriate structure modifications.
Asunto(s)
Benzodiazepinas/farmacología , Receptores de Colecistoquinina/metabolismo , Receptores Opioides/metabolismo , Animales , Benzodiazepinas/síntesis química , Encéfalo/metabolismo , Corteza Cerebral/metabolismo , Fenómenos Químicos , Química , Colecistoquinina/metabolismo , Dihidromorfina/metabolismo , Cobayas , Estructura Molecular , Naloxona/metabolismo , Páncreas/metabolismo , Ratas , Receptores Opioides kappa , Sincalida/metabolismoRESUMEN
Chain modification of a thiazolidinone prostaglandin isostere has led to the production of 4-[3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl] benzoic acid (5b) which at 1 mg/kg po in the conscious dog causes a 70% increase in renal blood flow over control values with a duration of action exceeding 5 h. Preliminary testing indicates that 5b has a relatively specific action on the vasculature of the kidney. The enantiomers of 5b have been separated and the renal vasodilatory activity has been found to be entirely a property of the R-(+) enantiomer.
Asunto(s)
Riñón/irrigación sanguínea , Tiazoles/farmacología , Vasodilatación/efectos de los fármacos , Animales , Perros , Femenino , Modelos Moleculares , Flujo Sanguíneo Regional/efectos de los fármacos , Estereoisomerismo , Tiazolidinas , Resistencia Vascular/efectos de los fármacos , Difracción de Rayos XRESUMEN
A series of 3-(arylureido)-5-phenyl-1,4-benzodiazepines, nonpeptidal antagonists of the peptide hormone cholecystokinin (CCK), are described. Derived by reasoned modification of the CCK-A selective 3-carboxamido-1,4-benzodiazepine, MK-329, this paper chronicles the development of potent, orally effective compounds in which selectivity for the CCK-B receptor subtype was achieved. The principal lead structure that emerged from these studied is L-365,260, a compound which has been submitted for clinical evaluation. Details of the ability to modulate the receptor interactions of these benzodiazepines by appropriate structure modifications are discussed which imply the possibility of further refining the CCK-B receptor affinity and selectivity of this class of compounds.
Asunto(s)
Benzodiazepinas/síntesis química , Benzodiazepinonas/síntesis química , Compuestos de Fenilurea , Receptores de Colecistoquinina/antagonistas & inhibidores , Animales , Benzodiazepinas/farmacocinética , Benzodiazepinas/farmacología , Benzodiazepinonas/química , Benzodiazepinonas/farmacocinética , Benzodiazepinonas/farmacología , Disponibilidad Biológica , Corteza Cerebral/metabolismo , Devazepida , Cobayas , Estructura Molecular , Páncreas/metabolismo , Ratas , Sincalida/metabolismo , Relación Estructura-ActividadRESUMEN
The first nonpeptide antagonists of the neurohypophyseal hormone, oxytocin (OT) are described. Derivatives of the spiroindenepiperidine ring system, these compounds include L-366,509, an orally bioavailable OT antagonist with good in vivo duration. The potential use of these agents for treatment of preterm labor and their significance as new nonpeptide ligands for peptide receptors are discussed.
Asunto(s)
Oxitocina/antagonistas & inhibidores , Piperidinas/farmacología , Compuestos de Espiro/farmacología , Administración Oral , Animales , Disponibilidad Biológica , Femenino , Espectroscopía de Resonancia Magnética , Trabajo de Parto Prematuro/tratamiento farmacológico , Piperidinas/administración & dosificación , Piperidinas/uso terapéutico , Embarazo , Ratas , Receptores de Angiotensina/metabolismo , Receptores de Oxitocina , Receptores de Vasopresinas/metabolismo , Compuestos de Espiro/administración & dosificación , Compuestos de Espiro/uso terapéutico , Relación Estructura-ActividadRESUMEN
A series of 3-substituted 5-phenyl-1,4-benzodiazepines, nonpeptidal antagonists of the peptide hormone cholecystokinin (CCK), have been synthesized. Designed on the basis of facts regarding CCK, its natural-product antagonist asperlicin (3), and the antianxiety agent diazepam (4), these compounds represent a significant departure from existing CCK antagonists. They also constitute perhaps the first examples of simple, nonpeptidal ligands for a peptide receptor to arise by design rather than by screening. These compounds serve to illuminate the distinction between central and peripheral CCK receptors, as well as to provide orally effective CCK antagonists of potential pharmacological or therapeutic utility. One rationale for their receptor affinity has possible applications in the design of nonpeptidal ligands for other receptors, peptidal as well as nonpeptidal.
Asunto(s)
Benzodiazepinas/síntesis química , Colecistoquinina/antagonistas & inhibidores , Receptores de Colecistoquinina/análisis , Animales , Ansiolíticos , Benzodiazepinas/metabolismo , Cobayas , Ligandos/síntesis química , Ratas , Receptores de GABA-A/análisis , Relación Estructura-ActividadRESUMEN
Seventeen analogues of the selective, competitive cholecystokinin (CCK) antagonist asperlicin 1 were prepared. These compounds were tested as inhibitors of the binding of [125I]CCK to rat pancreas and guinea pig brain receptors. Compounds 4, 7, and 8 were more potent than asperlicin on the pancreatic CCK receptor. One analogue, 17, displayed potency equivalent to asperlicin on the pancreas CCK receptor and showed a marked improvement in aqueous solubility, thereby facilitating the use of this class of CCK antagonists in physiological and pharmacological studies.
Asunto(s)
Benzodiazepinonas/síntesis química , Colecistoquinina/antagonistas & inhibidores , Animales , Benzodiazepinonas/farmacología , Cobayas , Técnicas In Vitro , Ratas , Receptores de Colecistoquinina/efectos de los fármacos , Solubilidad , Relación Estructura-ActividadRESUMEN
Nineteen tetrapeptides containing statine (Sta) and 4-amino-5-cyclohexyl-3-hydroxypentanoic acid (ACHPA) were prepared. Solubility measurements of these compounds were carried out in H2O and in pH 7.4 phosphate buffer solution, and their partition coefficients were determined in a 1:1 1-octanol/sodium phosphate-citric acid buffer system. The tetrapeptides were tested in vitro for their ability to inhibit porcine, canine, and human plasma renins. Four compounds, 6, 12, 14, and 20, were potent inhibitors against all renins tested (IC50 = 10(-9) M). Compound 12 was administered orally to dogs and substantially inhibited plasma renin activity for up to 5 h. The addition of polar groups to the C-terminus of Sta- and ACHPA-containing tetrapeptides renders them soluble in aqueous milieu and provides a valuable tool with which to examine the role of the renin-angiotensin system in physiological and pathological circumstances.
Asunto(s)
Oligopéptidos/síntesis química , Renina/antagonistas & inhibidores , Aminoácidos/farmacología , Animales , Perros , Humanos , Oligopéptidos/farmacología , Solubilidad , Relación Estructura-Actividad , PorcinosAsunto(s)
Benzodiazepinas/síntesis química , Benzodiazepinas/metabolismo , Benzodiazepinonas , Compuestos de Fenilurea , Receptores de Colecistoquinina/metabolismo , Animales , Benzodiazepinas/farmacología , Unión Competitiva , Encéfalo/metabolismo , Gastrinas/metabolismo , Cobayas , Ligandos , Ensayo de Unión Radioligante , Ratas , Relación Estructura-ActividadAsunto(s)
Oxitocina/antagonistas & inhibidores , Péptidos Cíclicos/farmacología , Receptores de Angiotensina/efectos de los fármacos , Secuencia de Aminoácidos , Animales , Femenino , Riñón/efectos de los fármacos , Cinética , Hígado/efectos de los fármacos , Datos de Secuencia Molecular , Oligopéptidos , Péptidos Cíclicos/síntesis química , Ratas , Receptores de Oxitocina , Streptomyces , Útero/efectos de los fármacosAsunto(s)
Aminas/síntesis química , Benzodiazepinas/síntesis química , Colecistoquinina/antagonistas & inhibidores , Aminas/farmacología , Animales , Benzodiazepinas/farmacología , Corteza Cerebral/metabolismo , Colecistoquinina/metabolismo , Mucosa Gástrica/metabolismo , Cobayas , Indicadores y Reactivos , Espectroscopía de Resonancia Magnética , Ratas , Receptores de Colecistoquinina/efectos de los fármacos , Receptores de Colecistoquinina/metabolismo , Relación Estructura-ActividadAsunto(s)
Oxitocina/antagonistas & inhibidores , Péptidos Cíclicos/síntesis química , Receptores de Angiotensina/efectos de los fármacos , Receptores de Vasopresinas , Secuencia de Aminoácidos , Animales , Arginina Vasopresina/metabolismo , Membrana Celular/metabolismo , Femenino , Indicadores y Reactivos , Riñón/metabolismo , Hígado/metabolismo , Datos de Secuencia Molecular , Estructura Molecular , Oxitocina/metabolismo , Péptidos Cíclicos/farmacología , Ratas , Receptores de Angiotensina/metabolismo , Receptores de Oxitocina , Solubilidad , Relación Estructura-Actividad , Útero/metabolismoRESUMEN
We describe the design and synthesis of nonpeptidal antagonists of the peptide hormone cholecystokinin. Several of these compounds have high specificity and nanomolar binding affinity and are active after oral administration. To our knowledge, the design of such agents has not previously been accomplished for any peptide hormone. The structural similarities between these synthetic compounds and the anxiolytic 1,4-benzodiazepines are noted, and the potential of this structural feature for future design of ligands for other peptide hormone receptors is discussed.
Asunto(s)
Benzodiazepinas/farmacología , Colecistoquinina/antagonistas & inhibidores , Animales , Benzodiazepinas/síntesis química , Unión Competitiva , Páncreas/metabolismo , Ensayo de Unión Radioligante , Ratas , Receptores de Superficie Celular/metabolismo , Receptores de Colecistoquinina , Relación Estructura-ActividadRESUMEN
The anti-anxiety agent ipsapirone has been shown to have modest affinity for alpha-1 receptors. We disclose the discovery of potent alpha-1a receptor subtype selective antagonists based on the ipsapirone structure which possess selectivity versus the 5-HT receptors tested. These antagonists were obtained by tethering a saccharin ring to 4-phenyl-3-carboxyethyl piperidines. The design principles which led to this structural motif are discussed. The synthesis of key analogs, their SAR, as well as results of selected in vitro and in vivo studies are described.
Asunto(s)
Antagonistas de Receptores Adrenérgicos alfa 1 , Antagonistas Adrenérgicos alfa/síntesis química , Pirimidinas/química , Animales , Ansiolíticos/química , Ansiolíticos/metabolismo , Diseño de Fármacos , Encefalina Ala(2)-MeFe(4)-Gli(5) , Encefalinas/metabolismo , Humanos , Masculino , Modelos Químicos , Hiperplasia Prostática/tratamiento farmacológico , Pirimidinas/metabolismo , Ratas , Receptores Adrenérgicos alfa 1 , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
We disclose a new compound class of potent and selective alpha-1A adrenergic receptor antagonists exemplified by the geminally, disubstituted cyclic imide 7. The optimization of lead compounds resulting in the cyclic imide motif is highlighted. The results of in vitro and in vivo studies of selected compounds are presented.
Asunto(s)
Antagonistas de Receptores Adrenérgicos alfa 1 , Animales , Perros , Semivida , Imidas/sangre , Imidas/síntesis química , Imidas/farmacocinética , Masculino , Piperidinas/síntesis química , Piperidinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Sensibilidad y EspecificidadRESUMEN
A novel class of potent and selective alpha-1a receptor antagonists has been identified. The structures of these antagonists were derived from truncating the 4-aryl dihydropyridine subunit present in known alpha-1a antagonists. The design principles which led to the discovery of substituted phenylacetamides, the synthesis and SAR of key analogues, and the results of select in vitro and in vivo studies are described.