Synthesis, β-adrenoceptor pharmacology and toxicology of S-(-)-1-(4-(2-ethoxyethoxy)phenoxy)-2-hydroxy-3-(2-(3,4-dimethoxyphenyl) ethylamino)propane hydrochloride, a short acting β₁-specific antagonist

The synthesis of S-(-)-1-(4-(2-ethoxyethoxy)phenoxy)-2-hydroxy-3-(2-(3,4-dimethoxyphenyl) ethylamino)propane hydrochloride (D140S·HCl 6), a novel short acting β₁-specific adrenoceptor antagonist, has been described. The antagonist potency for D140S·HCl 6 has been compared with esmolol, another short acting agent, and other well known β-adrenoceptor antagonists in isolated rat tissue preparations. The pharmacokinetics of D140S·HCl 6 in 7 day continuous intravenous infusions and 4 weeks intravenous bolus injection studies in conscious rats and dogs have been examined in toxicology studies. The effect on the isoprenaline-induced heart rate increase and the pharmacodynamic half-life of D140S·HCl 6 has been compared with esmolol in a conscious rat model. In addition, the results of a range of toxicological studies are presented. The results indicate that D140S·HCl 6 is a highly specific β₁-adrenoceptor antagonist (pA₂=8.15±0.22, β₁/β₂ selectivity>4400). The in vitro studies suggest D140S·HCl is ca. ten times more potent and 60 times more β₁-specific than racemic esmolol. Pharmacokinetic non-linearity was seen when given as a 7 day intravenous infusion at toxicological doses above 10 mg kg^-1 h^-1 in the rat and 2.5 mg kg^-1 h^-1 in the dog. Both D140S·HCl 6 and esmolol have very short durations of action after intravenous infusion in the rat (pharmacodynamic half-life is <15 min for D140S·HCl and 10 min for esmolol). The toxicological tests indicate that D140S·HCl 6 shows no unexpected toxicity and none of the tissue irritancy problems reported for esmolol formulations.