title: Brain pharmacokinetics of two prolyl oligopeptidase inhibitors, JTP-4819 and KYP-2047, in the rat.
abstract: Prolyl oligopeptidase (PREP) inhibitors are potential drug candidates for the treatment of neurological disorders, but little is known about their ability to cross the blood-brain barrier and to reach the target site. This study characterizes brain pharmacokinetics of two potent PREP inhibitors, JTP-4819 and KYP-2047. Firstly, the in vitro permeability (P(app) ) of JTP-4819 and KYP-2047 through a bovine brain microvessel endothelial cell monolayer was assessed. Then, the in vivo brain/blood ratio was determined for the total brain and plasma concentrations and also for the unbound extracellular drug concentrations after a single dose (50 μmol/kg i.p.). KYP-2047 had a significantly higher P(app)  than JTP-4819. In vivo, KYP-2047 had higher total and unbound brain/blood ratios. KYP-2047 was equally distributed between the cortex, hippocampus and striatum. In the case of JTP-4819, the unbound brain extracellular concentrations could not be readily predicted from the unbound blood levels, probably because of its poor membrane penetration properties. KYP-2047 displayed a better ability to reach the intracellularly located brain PREP, and it inhibited this enzyme more effectively than JTP-4819 after an equimolar single dose. In conclusion, KYP-2047 showed better brain penetration characteristics than JTP-4819 both in vitro and in vivo. KYP-2047 is a brain-penetrating, potent and long-acting PREP inhibitor; thus, it represents a convenient pharmacological tool for assessing the potential of PREP as a drug target.
authors.affiliation: School of Pharmacy, University of Eastern Finland, Kuopio. Aaro.Jalkanen@uef.fi
authors.forename: Aaro J
authors.initials: AJ
authors.lastname: Jalkanen
authors.forename: Jenni J
authors.initials: JJ
authors.lastname: Hakkarainen
authors.forename: Marko
authors.initials: M
authors.lastname: Lehtonen
authors.forename: Tetta
authors.initials: T
authors.lastname: Venäläinen
authors.forename: Tiina M
authors.initials: TM
authors.lastname: Kääriäinen
authors.forename: Elina
authors.initials: E
authors.lastname: Jarho
authors.forename: Marjukka
authors.initials: M
authors.lastname: Suhonen
authors.forename: Markus M
authors.initials: MM
authors.lastname: Forsberg
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D001921:Brain / Q000098:blood supply / Q000201:enzymology / Q000378:metabolism*; D002199:Capillary Permeability; D002853:Chromatography, Liquid; D004353:Drug Evaluation, Preclinical; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D017551:Microdialysis; D055806:Microvessels / Q000166:cytology; D015394:Molecular Structure; D011392:Proline / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D000085822:Prolyl Oligopeptidases; D011759:Pyrrolidines / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: C551540:4-phenylbutanoyl-prolylcyanopyrrolidine; D011759:Pyrrolidines; D015842:Serine Proteinase Inhibitors; D011392:Proline; C094211:JTP 4819; D012697:Serine Endopeptidases; D000085822:Prolyl Oligopeptidases