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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.

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Whereas nausea and emesis are burdensome side effects that lead to poor treatment compliance especially in chemotherapy, it is difficult to predict the emetic potential of agents in rats and mice because rodents do not vomit. We examined the effect of emetics on gastric retention and role of serotonin (5-hydroxytryptamine, 5-HT)3 receptor in chemotherapeutic-induced enhancement of gastric retention in rats. The gastric retention of solid material was determined using resin beads, which were suitable to beads made with metals or glasses in size, hardness and weight. Each rat was orally given distilled water (0.5 ml/rat) containing 40 resin beads via a plastic feeding tube. The stomach was removed at 1 hr post-dose and cut along the greater curvature under carbon dioxide anesthesia. Beads were given immediately after administration of the drugs except with cisplatin, when there was a 1 hr delay. Cancer chemotherapeutics including cisplatin(0.1-3 mg/kg i.v.) and doxorubicin(0.3-10 mg/kg i.v.) and a nauseant, copper sulfate(1-30 mg/kg p.o.) enhanced gastric retention of beads. Ondansetron, a 5-HT3 receptor antagonist, dose-dependently antagonized the enhanced gastric retention by cisplatin and doxorubicin. The copper sulfate-induced enhancement was also reversed by ondansetron. Our results suggest that 5-HT3 receptors mediate the cancer chemotherapeutic-enhanced gastric retention of solid material in rats. This implicates that the gastric retention of solid material is a useful marker to predict the potential of compounds to induce nausea and/or emesis in non-vomiting rodents.

-In order to better understand the variability of pharmacodynamic and pharmacokinetic profiles of terfenadine between the previous studies as well as to qualitatively and quantitatively examine the proarrhythmic potential of its major active metabolite fexofenadine in comparison with that of terfenadine, we directly compared their electropharmacological effects with halothane-anesthetized dogs (n = 3). For this purpose, we adopted a cross-over design, which can directly compare the effects of terfenadine and fexofenadine under the identical metabolic condition. Terfenadine in doses of 0.03 and 0.3 mg/kg increased the mean blood pressure, but that of 3 mg/kg decreased it. Terfenadine also increased the heart rate and ventricular contractility in a dose-related manner; but delayed the atrioventricular nodal and intraventricular conductions as well as repolarization suggesting its proarrhythmic potential. Meanwhile, fexofenadine in the same dose increased the mean blood pressure in a dose-related manner without affecting any of the electrophysiological variables in the same animals that proarrhythmic risk of terfenadine was confirmed, indicating its lack of proarrhythmic risk. Peak plasma concentrations for fexofenadine were 3.7, 8.1 and 11.2 times greater than for terfenadine at each matching dose, indicating terfenadine may be metabolized much faster than fexofenadine. Taken together, after the low and middle doses of terfenadine, vasopressor effect of a metabolite fexofenadine could be greater than the depressor effect of parent compound terfenadine, but its reverse would be correct after the high dose. Thus, the cross-over analysis can be an effective way to better understand drug-induced cardiovascular responses.