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Title: Synthesis, beta-adrenoceptor pharmacology and toxicology of S-(-)-1-(4-(2-ethoxyethoxy)phenoxy)-2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethylamino)propane hydrochloride, a short acting beta(1)-specific antagonist.
Austin Authors: Jackman, Graham P;Iakovidis, Dimitri;Nero, Tracy L;Anavekar, Nagesh S;Rezmann-Vitti, Linda A;Louis, Simon N S;Mori, Masanori;Drummer, Olaf H;Louis, William J 
Affiliation: Clinical Pharmacology and Therapeutics Unit, Department of Medicine, Austin and Repatriation Medical Centre, The University of Melbourne, Heidelberg, Vic 3084, Australia
Issue Date: 1-Sep-2002
Publication information: European Journal of Medicinal Chemistry; 37(9): 731-41
Abstract: 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 beta(1)-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 beta-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 beta(1)-adrenoceptor antagonist (pA(2) = 8.15+/-0.22, beta(1)/beta(2) selectivity > 4400). The in vitro studies suggest D140S.HCl is ca. ten times more potent and 60 times more beta(1)-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.
Gov't Doc #: 12350290
Journal: European journal of medicinal chemistry
Type: Journal Article
Subjects: Adrenergic beta-1 Receptor Agonists
Adrenergic beta-Agonists.chemical synthesis.pharmacology.toxicity
Adrenergic beta-Antagonists.pharmacology
Chromatography, High Pressure Liquid
Heart Atria.drug effects
In Vitro Techniques
Infusions, Intravenous
Magnetic Resonance Spectroscopy
Myocardial Contraction.drug effects
Propane.analogs & derivatives.chemical synthesis.pharmacology
Rats, Sprague-Dawley
Trachea.drug effects
Appears in Collections:Journal articles

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