The effects of mevinolin, a 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitor and bezafibrate, a modulator of lipoprotein metabolism, were measured on BM 15.766-induced 7-dehydrocholesterol (7-DHC) accumulation in liver and serum of rats. BM 15.766, an inhibitor of delta 7 sterol reductase, leads to an accumulation of 7-DHC, which can be used as a measure of cholesterol (CH) synthesis de novo. The investigations were carried out to evaluate the usefulness of this new non-isotopic in vivo method for testing compounds that affect directly and indirectly the CH-biosynthetic pathway. Mevinolin showed a dose-dependent reduction of BM 15.766-induced 7-DHC accumulation after a single oral dose. The dose range for reduction of 7-DHC in the liver of rats was comparable with that for serum CH-lowering in humans. Bezafibrate reduced the BM 15.766-induced 7-DHC accumulation in liver in a dose- and time-dependent manner. These findings agree with the reported reduced activity of HMG-CoA reductase and support the view, that bezafibrate reduces CH biosynthesis by modulation of lipoprotein metabolism. The 7-DHC levels in serum do not reflect those in the liver and cannot be used as a measure of CH biosynthesis. The investigations show that BM 15.766-induced 7-DHC accumulation in liver of rats is an appropriate measure for CH de novo synthesis and can be used for testing compounds that interfere directly and indirectly with the CH-biosynthetic pathway. In contrast to previously described methods, no radiolabelled precursors are necessary.(ABSTRACT TRUNCATED AT 250 WORDS)
Durch Addition von Blausaure an Thiazoline-A3 erhalt man die Thiazolidin-nitrile-(4) 1 -14 (Tab. l), welche sich bei Vorhandensein geeigneter Substituenten zu Thiazolidin-amiden-(4) 15-23 (Tab. 2), -thioamiden-(4) 24-31 (Tab. 3) und -carbonsauren-(4) 35-37 umsetzen lassen. Durch hydrolytische Ringspaltung dieser Folgeprodukte gelingt die Darstellung der bisher unbekannten Penicillamin-Derivate 32-34. -Die Addition von Blausaure an Thiazoline-A4 wird beschrieben.
4-Substit. Thiazolidin-Derivate
NitrileBei der Einwirkung von Blausaure auf Thiazoline-A3 entstehen in exothermer Reaktion farblose, kristalline Thiazolidin-nitrile-(4) von oft nur geringer Bestandigkeit I,*).
CNDie meisten der bisher untersuchten Thiazolidin-nitrile-(4) zersetzen sich an der Luft unter Abgabe von Blausaure und Bildung brauner, schmieriger Massen. Durch Umwandlung in Hydrochloride lassen sie sich stabilisieren. Aus Tabelle 1 erkennt man, daR zwischen Ausbeute bzw. Bestandigkeit einerseits und Anzahl, Art sowie Stellung der Substituenten am Thiazolin-A3-System andererseits kein eindeutiger Zusammenhang besteht. Die Bestandigkeit der Nitrile ist auRerordentlich von der Reinheit der Praparate abhangig.
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