Synthesis, Characterization, and Ca2+ Antagonistic Activity of Diltiazem Metabolites

Li Rongshi, Patrick S. Farmer, Pollen K.F. Yeung, Mei Xie, Michael A. Quilliam, Stephen Pleasance, Susan E. Hewlett

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29 Scopus citations


Diltiazem is a calcium antagonist widely used in the treatment of angina and hypertension. The contributions of metabolites of diltiazem to the vasorelaxant effects of diltiazem were investigated. The synthesis and spectroscopic characterization of eight major cts-diltiazem metabolites are described. Three of the compounds—N, O-didemethylated metabolite (21), O-demethylated metabolite (22), and diltiazem N-oxide (27)—have been recently reported and have not previously been synthesized. The identities of all eight synthetic metabolites have been verified with samples obtained from human urine using combined LC-MS/MS. The Ca2+ antagonistic activities of diltiazem and its metabolites (except 27) were studied on hamster arota preparations depolarized with KCl. The order of potencies (IC50 ± SE, μ M) is as follows: diltiazem (0.98 ± 0.47) > 17 (2.46 ± 0.38) ≥ 23 (3.27 ± 1.02) > 26 (20.2 ± 10.5) 22 (40.4 ± 15.4) > 25 (45.5 ± 18.1) > 21 (112.2 ± 33.2) ≥ 24 (126.7 ± 24.2). Structure-activity relationships are also discussed.

Original languageEnglish (US)
Pages (from-to)3246-3253
Number of pages8
JournalJournal of Medicinal Chemistry
Issue number17
StatePublished - Aug 1 1992
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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