1. Academic Validation
  2. A new class of selective and potent 7-dehydrocholesterol reductase inhibitors

A new class of selective and potent 7-dehydrocholesterol reductase inhibitors

  • J Med Chem. 2012 Sep 13;55(17):7614-22. doi: 10.1021/jm3006096.
Aline Horling 1 Christoph Müller Richard Barthel Franz Bracher Peter Imming
Affiliations

Affiliation

  • 1 Institut für Pharmazie, Martin-Luther-Universität Halle-Wittenberg , Wolfgang-Langenbeck-Strasse 4, 06120 Halle, Germany.
Abstract

We prepared a number of N-phenethyltetrahydroisoquinolines structurally related to protoberberines. They were tested for activity against bacteria, fungi, and human leukemia HL-60 cells and also for inhibition of biosynthesis: ergosterol in yeasts and Cholesterol in human cells. In the latter assay panel, several of the compounds were distinguished by a strong and selective inhibition of 7-dehydrocholesterol reductase (7-DHCR, EC 1.3.1.21), an Enzyme responsible for the conversion of 7-dehydrocholesterol to Cholesterol in the last step of Cholesterol biosynthesis. In a whole-cell assay, the most active compound 5f showed a much stronger inhibition of overall Cholesterol biosynthesis (IC(50) 2.3 nM) than BM 15.766 (IC(50) 500 nM), presently the most selective known inhibitor of 7-DHCR. Since a defect of 7-dehydrocholesterol reductase is associated with Smith-Lemli-Opitz syndrome (SLOS), the potent and selective inhibitors reported here will enable more detailed investigation of the pathogenesis of SLOS.

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