RESUMEN
A series of 2-substituted 2-aminopropane-1,3-diols having a biphenyl moiety and their phosphate esters were synthesized to obtain sphingosine 1-phosphate receptor-1 (S1P(1)) receptor agonists with potent immunomodulatory activity accompanied by little or no effect on heart rate. Many of the synthesized compounds sufficiently decreased the number of peripheral blood lymphocytes. Some of the phosphates had potent agonism at S1P(1) but no agonism at S1P(3), which had been reported to be a receptor responsible for heart rate reduction. Although high S1P(1)/S1P(3) selectivity was considered to be favorable to reduce the effect on heart rate, almost all the phosphates showed a remarkable heart rate lowering effect in vivo. The results suggest that other factors in addition to S1P(3) agonism should be responsible for the heart rate reduction caused by S1P(1) agonists. Only 2-amino-2-[2-[2'-fluoro-4'-(4-methylphenylthio)biphenyl-4-yl]ethyl]propane-1,3-diol (6d) was identified as a desired S1P(1) receptor agonist having both the immunomodulatory activity and an attenuated effect on heart rate by a unique screening flow using in vivo evaluating systems primarily.
Asunto(s)
Compuestos de Bifenilo/síntesis química , Frecuencia Cardíaca/efectos de los fármacos , Factores Inmunológicos/síntesis química , Propanolaminas/síntesis química , Glicoles de Propileno/síntesis química , Receptores de Lisoesfingolípidos/agonistas , Animales , Compuestos de Bifenilo/efectos adversos , Compuestos de Bifenilo/farmacología , Línea Celular , Cricetinae , Cricetulus , Factores Inmunológicos/efectos adversos , Factores Inmunológicos/farmacología , Recuento de Linfocitos , Masculino , Ratones , Ratones Endogámicos BALB C , Propanolaminas/efectos adversos , Propanolaminas/farmacología , Glicoles de Propileno/efectos adversos , Glicoles de Propileno/farmacología , Ratas , Ratas Endogámicas F344 , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
A practical asymmetric synthesis of both enantiomers of the immunosuppressive FTY720-phosphate (2) was accomplished, and the enantiomers were pharmacologically evaluated. Several lipases showed considerable activity and enantioselectivity for O-acylation of N-acetyl FTY720 (3) or N-benzyloxycarbonyl FTY720 (7) in combination with vinyl acetate or benzyl vinyl carbonate as the acyl donors. The synthesis using the lipase-catalyzed acylation as the key step produced the enantiomerically pure (>99.5% ee) enantiomers of 2 in multigram quantities. (S)-Isomer of 2 had more potent binding affinities to S1P(1,3,4,5) and inhibitory activity on lymphocyte migration toward S1P than (R)-2, suggesting that (S)-isomer of 2 is responsible for the immunosuppressive activity after administration of 1. Severe bradycardia was observed in anesthetized rats when (S)-2 was administered intravenously, while (R)-2 had no clear effect on heart rate up to 0.3 mg/kg.
Asunto(s)
Inmunosupresores/síntesis química , Inmunosupresores/farmacología , Glicoles de Propileno/síntesis química , Glicoles de Propileno/farmacología , Animales , Línea Celular , Movimiento Celular/efectos de los fármacos , Clorhidrato de Fingolimod , Humanos , Inmunosupresores/metabolismo , Linfocitos/efectos de los fármacos , Ratones , Modelos Químicos , Estructura Molecular , Glicoles de Propileno/metabolismo , Unión Proteica , Ratas , Ratas Sprague-Dawley , Receptores de Lisoesfingolípidos/metabolismo , Esfingosina/análogos & derivados , EstereoisomerismoRESUMEN
BACKGROUND AND OBJECTIVES: Recently, early mobilization and discharge after cardiac surgery have been recommended. However, many patients are anxious about returning to daily life soon after undergoing heart operations. To resolve this problem, an individualized rehabilitation plan for each patient is important. Rehabilitation programs must estimate the level of cardiac function in daily life. This study evaluated self-measurements of heart rate and blood pressure during home-based exercise training. METHODS: Thirty-six patients, 28 men and 8 women (mean age 58 +/- 19 years) who underwent cardiac operations were enrolled in this study. None of the patients experienced postoperative complications. Changes in heart rate and blood pressure during daily activities at home were measured by the patients. This data was then used to plan individual rehabilitation programs. RESULTS: The blood pressure rose from 114 +/- 17 to 139 +/- 21 mmHg (mean increase of 25 +/- 15 mmHg) when the patients were asked to walk up and down a set of stairs. Thirteen patients (36%) exhibited an increase in blood pressure of 30 mmHg or more while ascending the stairs. The patients' blood pressure returned to its pre-exercise level after 5 min. The heart rate rose from 84 +/- 15 to 113 +/- 14 beats/min (mean increase of 29 +/- 8 beats/min) during the exercise. During the home-based training period, the maximum blood pressure was 133 +/- 22 mmHg, and the maximum heart rate was 97 +/- 13 beats/min. CONCLUSIONS: The patients were very careful during their trial outpatient period, as this was their first post-cardiac surgery experience. Consequently, the degree of exercise at home was even more mild than in hospital. Self-measurement of heart rate and blood pressure was feasible. By referring to these measurements, the patients were able to monitor and increase their level of exercise. This post-cardiac surgery rehabilitation program is helpful for early returning to daily life activities.