Soft Drugs VI. The Application of the Inactive Metabolite Approach for Design of Soft β-Blockers1?2

Nicholas Bodor, Yasuo Oshiro, Thorsteinn Loftsson, Michael Katovich, Robert William Caldwell

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

The “inactive metabolite approach” was used to design β-blockers. The acidic inactive metabolite of metoprolol [4-(2-hydroxy-3-isopropylamino) propoxyphenylacetic acid] was used as the lead compound. Its esters (alkyl and cycloalkyl) were found active in vivo while reverting quantitatively to the same inactive metabolite in plasma. The cyclohexyl ester showed the best activity, which was cardioselective, similar to the parent compound metoprolol. Although most esters had a plasma half-life of approximately 1 min, their activity (antagonism of isoproterenol induced increase in heart rate) following intravenous administration lasted 45–90 minutes, and the maximum β-blockade was observed at 45–60 minutes in both rats and dogs.

Original languageEnglish (US)
Pages (from-to)120-125
Number of pages6
JournalPharmaceutical Research: An Official Journal of the American Association of Pharmaceutical Scientists
Volume1
Issue number3
DOIs
StatePublished - May 1984
Externally publishedYes

ASJC Scopus subject areas

  • Biotechnology
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry
  • Pharmacology (medical)

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