RESUMEN
Renin inhibitors having 13 different isosteres connecting the P3 and P2 positions have been prepared. Synthetic routes and in vitro activity exhibited by these compounds are discussed. The two most potent compounds, 47 and 48, contained the hydroxyethylene isostere, psi [CHOHCH2], and had IC50 values of 61 and 22 nM, respectively.
Asunto(s)
Inhibidores de Proteasas/síntesis química , Renina/antagonistas & inhibidores , Antihipertensivos/síntesis química , Fenómenos Químicos , Química , Quimotripsina/metabolismo , Humanos , Hidrólisis , Técnicas In Vitro , Inhibidores de Proteasas/metabolismo , Relación Estructura-ActividadRESUMEN
A number of peptides and modified peptides were synthesized and studied for their ability to reverse electroconvulsive shock-induced amnesia in rodents. A few of these peptides were selected for secondary evaluation in tests of short-term memory in rats and aged rhesus monkeys. A number of the peptides and modified peptides were active in the amnesia reversal test. In selected secondary tests, however, the chosen compounds failed to show significant activity in enhancing memory. New methods for preparing methyleneamino and methyleneoxy isosteres of peptides are reported. Other modified peptides also included methylenethio, methylenesulfonyl, and ethylene isosteres in place of the normal peptide amide bond.
Asunto(s)
Cognición/efectos de los fármacos , Oxitocina/farmacología , Péptidos/farmacología , Vasopresinas/farmacología , Animales , Macaca mulatta , Memoria a Corto Plazo/efectos de los fármacos , Péptidos/síntesis química , Ratas , Relación Estructura-ActividadRESUMEN
Several small peptides related to neurotensin (NT) and tuftsin were synthesized and tested for analgesic activity against acetic acid induced writhing in mice. None of the peptides approached the activity shown by NT or NT hexapeptide. Tuftsin itself was found to be weakly active. An isosteric dipeptide related to a cobra venom peptide was found to have considerable anti-writhing activity at a high intracerebroventricular dose.
Asunto(s)
Analgésicos , Neurotensina/farmacología , Péptidos/farmacología , Tuftsina/farmacología , Animales , Fenómenos Químicos , Química , Cromatografía en Capa Delgada , Masculino , Ratones , Morfina/farmacología , Naloxona/farmacología , Péptidos/análisisRESUMEN
A new approach was developed for the synthesis of (S)-1-[5-(benzoylamino)-1,4-dioxo-6-phenylhexyl]-L-proline (1) and 23 analogues. The delta-(acylamino)-gamma-keto acid intermediates were obtained by a modified Dakin--West reaction using 3-carbomethoxypropionyl chloride. Acylation of L-proline and recrystallization of the mixture of diastereomers gave the optically pure title compound in three reaction steps. The in vitro angiotensin converting enzyme (ACE) inhibitory activity of 1 was confirmed. Some of the novel analogues (6, 11, 13, and 17) were also found to be potent inhibitors of ACE in vitro with an IC50 of 1.4-8.8 x 10(-9) M (IC50 for captopril = 0.9 x 10(-8) M). In vivo these compounds (6, 11, 17, and 18) were much less active than captopril, especially by the oral route. Against angiotensin I (AI) challenge in normotensive conscious rats, 1 and 6 produced less than 50% inhibition at 30 mg/kg po but 57 to 82% inhibition at 3 mg/kg iv. Inhibition by both routes lasted less than 1 h. In renal hypertensive rats, 1 and 15 of its analogues failed to produce significant blood pressure lowering effects, in contrast to the marked effects of captopril. Near maximum inhibition of AI was achieved by continuous intravenous infusions of 1 and 20, suggesting that limited oral activity may by due to degradation and/or clearance.
Asunto(s)
Dipéptidos/síntesis química , Oligopéptidos , Angiotensina II/metabolismo , Animales , Presión Sanguínea/efectos de los fármacos , Dipéptidos/farmacología , Relación Dosis-Respuesta a Droga , Masculino , Ratas , Relación Estructura-Actividad , TeprotidoRESUMEN
The synthesis and biological activities of a series of 12 new semisynthetic penicillins is described. These compounds consisted of acylated amino acid analogs of 6-substituted-1,2-dihydro-2-oxonicotinic acid and 2-substituted-3,4-dihydro-4-oxo-5-pyrimidinecarboxylic acid attached to amoxicillin. The effect of the amino acid substituent, chirality of amino acid and acyl function on biological properties is discussed.
Asunto(s)
Amoxicilina/análogos & derivados , Amoxicilina/farmacología , Bacterias/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Relación Estructura-ActividadRESUMEN
A series of des-His2 octa- and nonapeptide analogues of luliberin (luteinizing hormone-releasing hormone) with modifications in the 1 and 6 positions, and in some instances the 10 position, has been prepared. Some of these analogues are potent inhibitors of luliberin in vitro and in vivo. The use of ultraviolet absorption measurements for evaluating peptides containing tyrosine and tryptophan is described. An efficient synthesis of O-methyl-d-tyrosine is reported.