title: Benzimidazolium salts as small, nonpeptidic and BBB-permeable human prolyl oligopeptidase inhibitors.
abstract: Prolyl oligopeptidase (POP) is a cytosolic serine peptidase that hydrolyzes proline-containing peptides at the carboxy terminus of proline residues. This peptidase has gained importance as a target for the treatment of cognitive disturbances of patients with neuropsychiatric diseases. Our research addresses the identification of POP inhibitors from a small focused library of polar heterocyclic compounds arising from multicomponent reactions. Two selective POP-specific inhibitors were identified on the basis of their inhibition of dipeptidyl peptidase IV. The most active compounds were evaluated for their in vitro transport through the blood-brain barrier (BBB) using a parallel artificial membrane permeability assay. Our results show for the first time that benzimidazolium salts are new POP-inhibitory scaffolds with properties of solubility, specificity, and lipophilicity that may allow them to cross the BBB by passive diffusion. These findings constitute an excellent starting point to synthesize new POP inhibitors with enhanced properties.
authors.affiliation: Institute for Research in Biomedicine, Barcelona Science Park, Josep Samitier 1-5, 08028 Barcelona, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Tarragó
authors.forename: Carme
authors.initials: C
authors.lastname: Masdeu
authors.forename: Elena
authors.initials: E
authors.lastname: Gómez
authors.forename: Nicolás
authors.initials: N
authors.lastname: Isambert
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Lavilla
authors.forename: Ernest
authors.initials: E
authors.lastname: Giralt
mesh_terms: D001562:Benzimidazoles / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors; D006801:Humans; D020128:Inhibitory Concentration 50; D000085822:Prolyl Oligopeptidases; D012697:Serine Endopeptidases / Q000187:drug effects / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D001562:Benzimidazoles; D054873:Dipeptidyl-Peptidase IV Inhibitors; D015842:Serine Proteinase Inhibitors; D018819:Dipeptidyl Peptidase 4; D012697:Serine Endopeptidases; C000705287:PREPL protein, human; D000085822:Prolyl Oligopeptidases