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Hypocholesterolemic 3[beta]-benzyl-4-methyl-4-aza-5[alpha]-cholestane methiodide.

Since the mid-1950's, we have been developing procedures for and synthesizing target azasteroids and other heterocyclic steroids as potential medicinal substances. One goal was to develop novel steroids which might be effective hypocholesterolemic substances. 4,4-Disubstituted azacholestanes were selected as a priority It was anticipated that such derivatives might be effective by one or more of three mechanisms. They might (1) inhibit absorption from the GI tract by forming non-absorbable cholesterol complexes (2) complex bile acids making them unavailable to facilitate cholesterol absorption, or (3) inhibit cholesterol biosynthesis at the lanosterol step because of the presence of two methyl groups at this position.

The more potent hypocholesterolemic steroids developed were the 4,4-dimethyl-4-aza-cholestanes with nitrogen at position four. The most active of these was 3[beta]-benzyl-4-methyl-4-aza-5[alpha]-cholestane methiodide. Evidence was obtained that it acts by at least two of the proposed possible mechanisms. It appears that this quaternary salt is absorbed because of its in vivo activity. It had been postulated that bulk around the quaternary nitrogen produced by the benzyl group might provide sufficient lipid solubility for absorption. The synthesis as well as in vitro and in vivo data will be presented..

Norman J. Doorenbos, Dept. Pharmacal Sci., Auburn Univ., Auburn, AL 36849 and Masako Nakagawa, Hokkaido Univ., Saporro, Japan.
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Title Annotation:Health Sciences
Author:Doorenbos, Norman J.
Publication:Journal of the Alabama Academy of Science
Article Type:Brief Article
Date:Apr 1, 2003
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