title: Arylpiperidines as a new class of oxidosqualene cyclase inhibitors.
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.
authors.affiliation: Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians University, Butenandtstr. 5-13, 81377 Munich, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Keller
authors.affiliation: Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians University, Butenandtstr. 5-13, 81377 Munich, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Wolfgardt
authors.affiliation: Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians University, Butenandtstr. 5-13, 81377 Munich, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Müller
authors.affiliation: Department of Pharmacy, Eberhard-Karls University, Auf der Morgenstelle 8, 72076 Tübingen, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Wilcken
authors.affiliation: Department of Pharmacy, Eberhard-Karls University, Auf der Morgenstelle 8, 72076 Tübingen, Germany.
authors.forename: Frank M
authors.initials: FM
authors.lastname: Böckler
authors.affiliation: Department of Drug Science and Technology, University of Torino, Via Pietro Giuria, 9, 10125 Torino, Italy.
authors.forename: Simonetta
authors.initials: S
authors.lastname: Oliaro-Bosso
authors.affiliation: Department of Drug Science and Technology, University of Torino, Via Pietro Giuria, 9, 10125 Torino, Italy.
authors.forename: Terenzio
authors.initials: T
authors.lastname: Ferrante
authors.affiliation: Department of Drug Science and Technology, University of Torino, Via Pietro Giuria, 9, 10125 Torino, Italy.
authors.forename: Gianni
authors.initials: G
authors.lastname: Balliano
authors.affiliation: Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians University, Butenandtstr. 5-13, 81377 Munich, Germany. Electronic address: Franz.Bracher@cup.uni-muenchen.de.
authors.forename: Franz
authors.initials: F
authors.lastname: Bracher
mesh_terms: D000924:Anticholesteremic Agents / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D019751:Intramolecular Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D062105:Molecular Docking Simulation; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000924:Anticholesteremic Agents; D004791:Enzyme Inhibitors; D010880:Piperidines; C043383:1-piperideine; D002784:Cholesterol; D019751:Intramolecular Transferases; C021924:lanosterol synthase
keywords: Arylpiperidine; Docking experiments; Enzyme inhibitor; High energy intermediate; Oxidosqualene cyclase