Synthesis and β-Adrenergic Antagonist Activity of Stereoisomeric Practolol and Propranolol Derivatives

Article abstract of DOI:10.1021/jm00163a036

A series of stereoisomeric practolol and propranolol derivatives has been synthesized in which the N-isopropyl group of the drug was replaced by an asymmetric heptanoic acid terminated by a substituted p-toluidide of p-(tri-fluoromethyl)anilide.The asymmetric epoxide, 3-(p-acetamidophenoxy)-1,2-epoxypropane, was allowed to react with a preformed enantiomeric 6-aminoheptanoic acid amide to yield the stereoisomeric practolol congener derivatives.An asymmetric drug precursor epoxide was prepared from p-acetamidophenol and enantiomeric 3-(tosyloxy)-1,2-epoxypropane (the Sharpless epoxide).For the propranolol congener derivatives, the preformed asymmetric 6-aminoheptanoic acid amides were allowed to react with one of the enantiomers of 3-(1-naphthyloxy)-1,2-epoxypropane.This drug precursor epoxide was prepared either by combining 1-naphthol with enantiomeric 3-(tosyloxy)-1,2-epoxypropane (the Sharpless epoxide) or by combining 1-naphthol with enantiomeric 3-(tosyloxy)-1,2-propanediol followed by epoxidation.Pharmacological studies carried out for the practolol derivatives demonstrated a significant dependence of enhanced potency and tissue/subreceptor specificity on both the configuration of the drug asymmetric carbon and the configuration of the spacer asymmetric carbon.The compounds containing the S configuration at the drug asymmetric center and the R configuration at the spacer asymmetric carbon exhibited an increase in potency over the other stereoisomeric congener derivatives and the progenitor drug.For the propranolol congener derivatives, a large decrease in potency was observed for all of the stereoisomers over the progenitor drug.The propranolol stereoisomers containing the S configuration at the drug asymmetric center were more active than those containing the R configuration at that center.