Effects of KUR-1246, a selective uterine relaxant, on transplacental passage and transmigration to milk.

AIM: To evaluate the safety of KUR-1246 as a tocolytic agent, we determined the effects of its constant infusion on efficacy, transplacental passage, and transmigration to milk in pregnant or puerperal animals and compared them to the effects of ritodrine hydrochloride. METHODS: A balloon method was used to evaluate the inhibitory effects of KUR-1246 constant infusion on spontaneous uterine motility in pregnant rats. We also measured transplacental passage and transmigration to milk of KUR-1246 in pregnant and/or puerperal animals. KUR-1246 and ritodrine hydrochloride concentrations were quantified using a liquid chromatography-tandem mass spectrometry method. RESULTS: Constant infusion of KUR-1246 and ritodrine hydrochloride clearly inhibited spontaneous uterine motility in vivo. The ED50 value for KUR-1246 was 1.1 mg/kg/min, a potency which was approximately 40-fold greater than that of ritodrine hydrochloride. Transplacental passage (proportions of fetal plasma/maternal plasma) of KUR-1246 in pregnant rats and/or guinea pigs were approximately one-half to one-third of that of ritodrine hydrochloride. Transmigration of KUR-1246 to milk in puerperal rats disappeared by 48 h after injection. CONCLUSIONS: KUR-1246 is a promising drug for the treatment of preterm labor in obstetric practice because it is as efficacious as currently used agents yet less likely to produce direct effects on the fetus.

Cardiovascular effects of KUR-1246, a new tetrahydronaphthalen derivative beta2-adrenoceptor agonist and a selective uterine relaxant.

The aim of this study was to assess the cardiovascular effects of KUR-1246 (CAS 194785-31-4, (-)-bis(2-{[(2S)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(2-hydroxyethyl) phenyl] ethyl}amino)-1,2,3,4-tetrahydronaphthalen-7-yl]oxy}-N,N-dimethylacetamide)monosulfate), a new beta2-adrenoceptor agonist tocolytic agent. In conscious dogs, the intravenous administration of KUR-1246 at 0.1 and 1 microg/kg had no effects on blood pressure, heart rate or femoral artery blood flow. KUR-1246 at 10 and 100 microg/kg significantly decreased blood pressure and increased heart rate. In the electrocardiograms, KUR-1246 did not affect QT intervals or QTc. In addition, the cardiac effects of KUR-1246 were evaluated in in vitro electrophysiological studies. KUR-1246 at 10 micromol/L did not affect action potential parameters (the maximal upstroke velocity, resting membrane potential, action potential amplitude and action potential durations) in isolated papillary muscles of guinea pigs or in the human ether-a-go-go related gene (HERG) tail current recorded from stably transfected human embryonic kidney (HEK) 293 cells. On the basis of these results, the effects of KUR-1246 in conscious dogs on the cardiovascular system appear to be limited to changes in blood pressure and heart rate. Therefore, KUR-1246 is unlikely to provoke ventricular arrhythmias by delaying the ventricular repolarization.