title: In vitro and in vivo inhibition of prolyl endopeptidase.
abstract: Four derivatives of a known prolyl endopeptidase (PEP) inhibitor (N-[N-(phenyl)butyryl-L-propyl]pyrrolidine; SUAM-1221) were synthesized along with the parent compound. All five compounds were relatively potent, competitive inhibitors of rat brain and mouse brain and kidney PEP, with IC50S in the range of 3-27 nM. Ex vivo experiments showed that all compounds penetrated into the CNS and produced inhibition of brain PEP, although inhibition was not as great as in the periphery (kidney PEP). Each compound had a similar time course of duration, with maximum inhibition of brain PEP being achieved within 5-10 min after i.p. administration, with inhibition of brain PEP (up to 20%) still present 6 h after dosing. However, two of the compounds, SUAM-1221 and its amine derivative, had ED50S versus mouse brain PEP (1-3 mg/kg) an order of magnitude less than the other compounds (25-40 mg/kg). Administration of the amine compound resulted in a significant partial reversal of the deficit in memory performance produced by scopolamine.
authors.affiliation: Neuroscience Research Centre, Merck Sharp & Dohme Research Laboratories, Harlow, Essex, U.K.
authors.forename: J R
authors.initials: JR
authors.lastname: Atack
authors.forename: N
authors.initials: N
authors.lastname: Suman-Chauhan
authors.forename: G
authors.initials: G
authors.lastname: Dawson
authors.forename: J J
authors.initials: JJ
authors.lastname: Kulagowski
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D010450:Endopeptidases / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008568:Memory / Q000187:drug effects; D051379:Mice; D000085822:Prolyl Oligopeptidases; D011480:Protease Inhibitors; D011758:Pyrroles / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012601:Scopolamine / Q000494:pharmacology; D012697:Serine Endopeptidases
chemical_list: D011480:Protease Inhibitors; D011758:Pyrroles; C074327:N-(N-(phenyl)butyryl-L-prolyl)pyrrolidine; D012601:Scopolamine; D010450:Endopeptidases; D012697:Serine Endopeptidases; D000085822:Prolyl Oligopeptidases