There is evidence that aspirin in low doses favorably influences the course of pregnancy-induced hypertension, but the mechanism, although assumed to involve suppression of the production of thromboxane by platelets, has not been established. We performed a randomized study of the effect of the long-term daily administration of 60 mg of aspirin (n = 17) or placebo (n = 16) on platelet thromboxane A2 and vascular prostacyclin in women at risk for pregnancy-induced hypertension. Low doses of aspirin were associated with a longer pregnancy and increased weight of newborns. Serum levels of thromboxane B2, a stable product of thromboxane A2, were almost completely (greater than 90 percent) inhibited by low doses of aspirin. The urinary excretion of immunoreactive thromboxane B2 was significantly reduced without changes in the level of 6-keto-prostaglandin F1 alpha, a product of prostacyclin. Mass spectrometric analysis showed that aspirin reduced the excretion of the 2,3-dinor-thromboxane B2 metabolite--mainly of platelet origin--by 81 percent and of thromboxane B2, probably chiefly of renal origin, by 59 percent. The urinary excretion of 6-keto-prostaglandin F1 alpha and of its metabolite 2,3-dinor-6-keto-prostaglandin F1 alpha was not affected. Low doses of aspirin only partially (63 percent) reduced neonatal serum thromboxane B2. No hemorrhagic complications were observed in the newborns. Thus, in women at risk for pregnancy-induced hypertension, low doses of aspirin selectively suppressed maternal platelet thromboxane B2 while sparing vascular prostacyclin, but only partially suppressed neonatal platelet thromboxane B2, allowing hemostatic competence in the fetus and newborn.

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Although most epilepsies are adequately treated by conventional antiepileptic therapy, there remains an unfulfilled need for safer and more effective anticonvulsant agents. Starting from milacemide, a weak anticonvulsant, and trying to elucidate its mechanism of action, we discovered a structurally novel class of potent and preclinically safe anticonvulsants. Here we report the structure-activity relationship (SAR) study within this series of compounds. Different parts of the structural lead 2-[[4-(3-chlorobenzoxy)benzyl]amino]acetamide (6) were thus varied (Figure 1), and many potent anticonvulsants were found. As an outcome of this study, 57 ((S)-2-[[4-(3-fluorobenzoxy)benzyl]amino]propanamide methanesulfonate, PNU-151774E) emerged as a promising candidate for further development for its potent anticonvulsant activity and outstanding therapeutic indexes (TIs) in different animal tests.

The equilibrium and relative rate of rotamer interconversion around the bond joining the 2,2'-bipyrrolyl and pyrromethene moieties in a synthetic analogue of immunosuppressant prodigiosin are investigated as a function of pHapp in a water/acetonitrile mixture (1/1 by volume). Two chromatographically separable isomeric forms are obtained in acid solutions (pHapp < 4), whereas rapid interconversion occurs above neutrality. Furthermore, pH modulates the conformational preference of the molecule according to nitrogen protonation on the three pyrrole rings system (pKa = 7.2). At high pHapp (neutral form), the same conformer that is observed in pure acetonitrile prevails, whereas the other one is preferred by the protonated form. The nuclear magnetic resonance data indicate that the structures of the two conformers mainly differ in the value of the torsion angle around the aforementioned C-C bond. Kinetic and equilibrium data are quantitatively interpreted with a cyclic mechanism including two protonation (pKa1 = 8.23 +/- 0.03, pKa2 = 5. 4 +/- 0.2) and two conformational rearrangement steps. A molecular interpretation of the observed behavior includes, for the preferred conformer at low pH, formation of a new hydrogen bond between the exocyclic oxygen and the neighboring pyrrole NH upon protonation of the three pyrrole rings system.