RESUMEN
Some recent progress concerning the optimal combinations of Lewis acids and solvents for the synthesis of pyrimidine as well as purine nucleosides is reviewed. Furthermore, the novel condensation of persilylated free sugars and heterocyclic bases in the presence of trimethylsilyl triflate to the corresponding persilylated nucleosides is discussed.
Asunto(s)
Nucleósidos/química , Nucleósidos/síntesis química , Carbohidratos , Indicadores y Reactivos , Estructura MolecularAsunto(s)
Dinoprost/análogos & derivados , Prostaglandina D2/metabolismo , Prostaglandinas/síntesis química , Receptores Inmunológicos , Receptores de Prostaglandina/metabolismo , Animales , Unión Competitiva , Dinoprost/síntesis química , Dinoprost/metabolismo , Humanos , Prostaglandinas/farmacologíaAsunto(s)
Dinoprost/análogos & derivados , Prostaglandinas Sintéticas/farmacología , Animales , Unión Competitiva , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Presión Sanguínea/efectos de los fármacos , Dinoprost/metabolismo , Dinoprost/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Técnicas In Vitro , Cinética , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Oxígeno/metabolismo , Prostaglandina D2/metabolismo , Prostaglandina D2/farmacología , Prostaglandinas Sintéticas/metabolismo , Ratas , Receptores de Prostaglandina/metabolismoRESUMEN
Various chemically stable prostaglandin analogues were studied for their affinity towards the PGD2-receptor in human platelet membranes in order to define the requirements for specific ligand binding to this receptor. On replacing the 11- or 9-hydroxyl groups of PGF2 alpha by an 11 alpha- or 9 beta-chloro- or fluoro atom, stable prostaglandin analogues were obtained, which showed high affinity towards the PGD2-receptor. The lower side chain consisted of a 15-cyclohexyl group or of the natural 15-n-pentyl group, other substitutents decreased the affinity substantially. The highest PGD2-mimetic activity with a relative affinity of 0.5 to the PGD2-receptor was found in 9-deoxy-9 beta-chloro-16,17,18,19,20-pentanor-15-cyclohexyl-PGF2 alpha (ZK 110 841, compound 16 in Table 1). ZK 110 841 is a chemically stable crystalline substance, which is orally active and which might thus turn out to be an interesting tool for the study of PGD2-receptor interactions. Some other prostaglandin as well as prostacyclin analogues with a 15-cyclohexyl or 15-n-pentyl group exhibited in addition to their known high affinity to the PGE2-receptor of human uterine membranes or the PGI2-receptor of human platelets also affinities to the PGD2-receptor. Generally, the receptor affinities correlate with the activities as stimulators of adenylate cyclase and inhibitors of thrombin induced elevation of cytoplasmic free calcium as well as their ability to inhibit ADP-induced platelet aggregation. The PGI2-character regarding the effector systems prevails in compounds with affinity to both the PGI2- and PGD2-receptor. Compounds which bind to the PGE2- and PGD2-receptor show a flat dose response curve regarding platelet activation suggesting a mixture of pro- and antiaggregatory properties within these molecules.
Asunto(s)
Prostaglandina D2/farmacología , Prostaglandinas/metabolismo , Receptores Inmunológicos , Receptores de Prostaglandina/metabolismo , Adenilil Ciclasas/sangre , Plaquetas/enzimología , Plaquetas/metabolismo , Calcio/sangre , AMP Cíclico/sangre , Halógenos/metabolismo , Halógenos/farmacología , Humanos , Técnicas In Vitro , Agregación Plaquetaria/efectos de los fármacos , Prostaglandinas/farmacología , Ensayo de Unión RadioliganteAsunto(s)
Epoprostenol/síntesis química , Administración Oral , Animales , Unión Competitiva , Presión Sanguínea/efectos de los fármacos , Epoprostenol/administración & dosificación , Epoprostenol/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Iloprost , Técnicas In Vitro , Agregación Plaquetaria/efectos de los fármacos , Ratas , Receptores de Epoprostenol , Receptores de Prostaglandina/metabolismoRESUMEN
A novel carbacyclin derivative (16S)-13,14-dehydro-16,20-dimethyl-3-oxa-18,18,19,19-tetradehydro- 6a- carbaprostaglandin-I2 (3-oxa-analogue) has been synthesized in order to find chemically and metabolically stable prostacyclin-mimetics with a potency equal or even superior to PGI2. The 3-oxa-analogue was found to be stabilized against beta-oxidation, a main metabolic degradation step also for chemically stable PGI2-analogues. The compound is orally available and displays a long duration of 4.5-48 h of antiaggregatory and hypotensive action. The 3-oxa-analogue inhibits ADP-induced platelet aggregation with an IC50 of 3.0 nM. Following intravenous application the 3-oxa-analogue lowers diastolic blood pressure in a dose dependent manner, the ED20 being 0.1-0.2 micrograms/kg after injection and less than or equal to 0.05 micrograms/kg/min after infusion respectively. In vivo platelet aggregation is inhibited after i.v. infusion of the 3-oxa-analogue with an IC50 of 0.037 micrograms/kg/min. As compared to Iloprost, the 3-oxa-analogue is 5-12 fold more potent with respect to in vivo hypotensive and anti-aggregatory effects. The results of the present studies indicate that the 3-oxa-analogue has a pharmacological profile comparable to prostacyclin (PGI2) and Iloprost. Due to the fact that the 3-oxa-analogue is chemically and metabolically stable, long term oral treatment can be achieved in clinical conditions in which PGI2 and Iloprost have already been shown to be therapeutically useful principles.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Epoprostenol/farmacología , Hidroxiprostaglandina Deshidrogenasas/metabolismo , Hígado/metabolismo , Agregación Plaquetaria/efectos de los fármacos , Administración Oral , Animales , Antihipertensivos , Arritmias Cardíacas/fisiopatología , Epoprostenol/administración & dosificación , Epoprostenol/metabolismo , Frecuencia Cardíaca/efectos de los fármacos , Técnicas In Vitro , Masculino , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas , Receptores de Prostaglandina/metabolismoAsunto(s)
Prostaglandinas Sintéticas , Abortivos no Esteroideos/síntesis química , Animales , Antihipertensivos/síntesis química , Plaquetas/efectos de los fármacos , Broncodilatadores/síntesis química , Enfermedades Gastrointestinales/tratamiento farmacológico , Humanos , Prostaglandinas Sintéticas/síntesis química , Prostaglandinas Sintéticas/uso terapéuticoAsunto(s)
Fármacos Cardiovasculares/síntesis química , Epoprostenol/síntesis química , Prostaglandinas/síntesis química , Adenosina Difosfato/farmacología , Epoprostenol/farmacología , Humanos , Iloprost , Indicadores y Reactivos , Conformación Molecular , Agregación Plaquetaria/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
The synthesis is described of new 15,15-ethylene ketals of natural prostaglandins and prostaglandin analogues. Especially the crystalline trisamine salt of the 15,15-ethylene ketal of 15-dehydro-16-phenoxy-17,18,19,20-tetranorprostaglandin F2alpha is a very active inducer of luteolysis in laboratory animals and cattle.