Prediction of retention for sulfonamides in supercritical fluid chromatography.

Properties-retention studies were undertaken on a test library of sulfonamides using supercritical fluid chromatography with CO(2)-MeOH mobile phases (in the presence or absence of additive) and a 2-ethyl-pyridyl column. Taking a restricted range of retention ratios, k (10.98). From these relationships, the different retention characteristics of the analytes were calculated. Literature studies of quantitative structure-retention relationships (QSRR) showed that these characteristics can be correlated with simple molecular descriptors to derive equations predicting the retention behaviour of new compounds. Measured retention characteristics were found to correlate with total dipole moment, mu, molecular surface area, A, and the electronic charge on the most negatively charged atom, delta(min). The correlation of chromatographic measurements with calculated molecular descriptors may allow the prediction of the retention behaviour for an unknown compound provided its properties are known.

Discovery and development of a new class of potent, selective, orally active oxytocin receptor antagonists.

We report a novel chemical class of potent oxytocin receptor antagonists showing a high degree of selectivity against the closely related vasopressin receptors (V1a, V1b, V2). An initial compound, 7, was shown to be active in an animal model of preterm labor when administered by the intravenous but not by the oral route. Stepwise SAR investigations around the different structural elements revealed one position, the arenesulfonyl moiety, to be amenable to structural changes. Consequently, this position was used to introduce a variety of substituents to improve the physicochemical properties. Some of the resulting analogues were found to be superior to 7 both in terms of potency in vitro and aqueous solubility, which translated into significantly improved efficacy in the animal model after intravenous and oral administration. The best compound, 73, potently inhibited oxytocin-induced uterine contractions in nonpregnant rats and reduced spontaneous uterine contractions in late-term pregnant rats.