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-benzothiazepin-4(5H)-one (LLU-beta1; 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.
Kantoci
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Department of Medicine, Loma Linda University, Loma Linda, California 92350, USA.
Murray
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Quiggle
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Wechter
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D000818:Animals; D002121:Calcium Channel Blockers / Q000378:metabolism*; D004110:Diltiazem / Q000378:metabolism*; D045283:Natriuretic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats
D002121:Calcium Channel Blockers; D045283:Natriuretic Agents; D004110:Diltiazem