Synthesis, characterization, and Ca2+ antagonistic activity of diltiazem metabolites

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DOIResolve DOI: http://doi.org/10.1021/jm00095a022
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TypeArticle
Journal titleJournal of Medicinal Chemistry
ISSN0022-2623
1520-4804
Volume35
Issue17
Pages32463253
AbstractDiltiazem 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 cis-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 aorta preparations depolarized with KCl. The order of potencies (IC50 +/- SE, microM) is as follows: diltiazem (0.98 +/- 0.47) greater than 17 (2.46 +/- 0.38) greater than or equal to 23 (3.27 +/- 1.02) greater than 26 (20.2 +/- 10.5) greater than 22 (40.4 +/- 15.4) greater than or equal to 25 (45.5 +/- 18.1) greater than 21 (112.2 +/- 33.2) greater than or equal to 24 (126.7 +/- 24.2). Structure-activity relationships are also discussed.
Publication date
LanguageEnglish
AffiliationNRC Institute for Marine Biosciences; National Research Council Canada
Peer reviewedNo
NPARC number23001023
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Record identifierf2c5784e-8a4c-46a6-9a2e-1a9407424342
Record created2016-11-29
Record modified2016-11-29
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