Arylpiperidines as a new class of oxidosqualene cyclase inhibitors

• Arylpiperidines are a new class of oxidosqualene cyclase inhibitors.
• They are steroidomimetic compounds mimicking cationic high energy intermediates.
• Compound 29 has submicromolar activity on human OSC and high species selectivity.
• This compound effectively reduces total cholesterol biosynthesis in a cellular assay.
• A plausible binding mode is suggested on the basis of docking experiments.

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.

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