Endogenous Natriuretic Factors. 5. Synthesis and Biological Activity of a Natriuretic Metabolite of Diltiazem and Its Derivatives

Endogenous Natriuretic Factors. 5. Synthesis and Biological Activity of a Natriuretic Metabolite of Diltiazem and Its Derivatives

In our search for endogenous natriuretic factors from human uremic urine, we have previously identified a new metabolite of the drug diltiazem (Murray et al. Life Sci. 1995, 57, 2145−2161). The structure of this metabolite, (+)-(2S,3S)-3-hydroxy-5-(2-hydroxyethyl)-2,3-dihydro-2-(4-methoxyphenyl)-1,5...

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Veröffentlicht in:Journal of medicinal chemistry 1996-03, Vol.39 (6), p.1196-1200
Hauptverfasser: Kantoci, Darko, Murray, E. David, Quiggle, David D, Wechter, William J
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Sprache:eng
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Animals
Calcium Channel Blockers - metabolism
Diltiazem - metabolism
Natriuretic Agents - chemical synthesis
Natriuretic Agents - pharmacology
Rats
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container_end_page 1200
container_issue 6
container_start_page 1196
container_title Journal of medicinal chemistry
container_volume 39
creator Kantoci, Darko
Murray, E. David
Quiggle, David D
Wechter, William J
description In our search for endogenous natriuretic factors from human uremic urine, we have previously identified a new metabolite of the drug diltiazem (Murray et al. Life Sci. 1995, 57, 2145−2161). The structure of this metabolite, (+)-(2S,3S)-3-hydroxy-5-(2-hydroxyethyl)-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one (LLU-β1; 2), was proved by unequivocal synthesis from a diltiazem synthon. The synthetic material also proved to be natriuretic as had the urinary isolate. Given the acetylation at C-3 in diltiazem, the 3-monoacetate (8) and diacetate (3) derivatives of 2 were prepared. The 4-nor-keto (6) derivative of 2 was also synthesized. Only the parent 2 induced natriuresis over a range of doses without accompanying kaliuretic activity at some doses.
doi_str_mv 10.1021/jm950559n
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subjects Animals
Calcium Channel Blockers - metabolism
Diltiazem - metabolism
Natriuretic Agents - chemical synthesis
Natriuretic Agents - pharmacology
Rats
title Endogenous Natriuretic Factors. 5. Synthesis and Biological Activity of a Natriuretic Metabolite of Diltiazem and Its Derivatives
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