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

J Med Chem. 1990 Jan;33(1):216-23. doi: 10.1021/jm00163a036.

Abstract

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 or p-(trifluoromethyl)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 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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adipose Tissue / drug effects
  • Adipose Tissue / metabolism
  • Adrenergic beta-Antagonists*
  • Animals
  • Biological Assay
  • Chemical Phenomena
  • Chemistry
  • Lymphoma / metabolism
  • Mice
  • Molecular Conformation
  • Molecular Structure
  • Practolol / analogs & derivatives*
  • Practolol / chemical synthesis
  • Practolol / pharmacology
  • Propranolol / analogs & derivatives*
  • Propranolol / chemical synthesis
  • Propranolol / pharmacology
  • Rats
  • Stereoisomerism
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • Adrenergic beta-Antagonists
  • Propranolol
  • Practolol