Synthesis and beta-adrenergic antagonist activity of stereoisomeric practolol and propranolol derivatives.
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.
Leftheris
K
K
Department of Chemistry, University of California, San Diego, La Jolla 92093.
Goodman
M
M
D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000319:Adrenergic beta-Antagonists; D000818:Animals; D001681:Biological Assay; D055598:Chemical Phenomena; D002621:Chemistry; D008223:Lymphoma / Q000378:metabolism; D051379:Mice; D008968:Molecular Conformation; D015394:Molecular Structure; D011217:Practolol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D011433:Propranolol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000319:Adrenergic beta-Antagonists; D011433:Propranolol; D011217:Practolol