2. Academic Validation
  3. Arylpiperidines as a new class of oxidosqualene cyclase inhibitors

Arylpiperidines as a new class of oxidosqualene cyclase inhibitors

  • Eur J Med Chem. 2016 Feb 15:109:13-22. doi: 10.1016/j.ejmech.2015.12.025.
Marco Keller 1,  Annette Wolfgardt 1,  Christoph Müller 1,  Rainer Wilcken 2,  Frank M Böckler 2,  Simonetta Oliaro-Bosso 3,  Terenzio Ferrante 3,  Gianni Balliano 3,  Franz Bracher 4
Affiliations

Affiliations

  • 1 Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians University, Butenandtstr. 5-13, 81377 Munich, Germany.
  • 2 Department of Pharmacy, Eberhard-Karls University, Auf der Morgenstelle 8, 72076 Tübingen, Germany.
  • 3 Department of Drug Science and Technology, University of Torino, Via Pietro Giuria, 9, 10125 Torino, Italy.
  • 4 Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians University, Butenandtstr. 5-13, 81377 Munich, Germany. Electronic address: Franz.Bracher@cup.uni-muenchen.de.
PMID: 26745812 DOI: 10.1016/j.ejmech.2015.12.025
Abstract

The cyclization of oxidosqualene to lanosterol, catalyzed by the enzyme oxidosqualene cyclase (OSC), goes through a number of carbocationic high energy intermediates (HEI), and mimicking these intermediates is a promising approach for the development of OSC inhibitors. 3-Arylpiperidines (or tetrahydropyridines) were designed as steroidomimetic rings A + C equivalents containing two protonable amino groups for mimicking both the pro-C4 HEI and the pro-C20 HEI of the OSC-mediated cyclization cascade. Inhibitory activity is strongly dependent on the nature of the lipophilic substituent representing an equivalent of the sterol side chain. Here aromatic residues (substituted benzyl, cinnamyl, naphthylmethyl) were found to be most suitable. Docking experiments on a first optimized 3-arylpiperidine compound led to an isomeric 4-arylpiperidine with submicromolar activity on human OSC. This inhibitor reduced total Cholesterol biosynthesis in a cellular assay with an IC50 value of 0.26 μM.

Keywords

Arylpiperidine; Docking experiments; Enzyme inhibitor; High energy intermediate; Oxidosqualene cyclase.

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