title: Binding kinetics and duration of in vivo action of novel prolyl oligopeptidase inhibitors.
abstract: Prolyl oligopeptidase (POP) is a serine protease that specifically hydrolyses small peptides at the carboxyl end of the proline residue. POP has gained pharmaceutical interest, since its inhibitors have been shown to have antiamnesic properties in rat. We examined the effect of the 2(S)-substituents CN and COCH(2)OH at the P1 site of the parent inhibitors isophthalic acid 2(S)-(cyclopentanecarbonyl)pyrrolidine-l-prolyl-pyrrolidine amide and 4-phenylbutanoyl-l-prolyl-pyrrolidine and bulky 5-t-butyl group at the P2 site l-prolyl residue of the parent inhibitor 4-phenylbutanoyl-l-prolyl-pyrrolidine on the binding kinetics to the enzyme. In addition, we studied the duration of POP inhibition in the rat tissues in vivo after i.p. administration. CN and COCH(2)OH substituents at the P1 site pyrrolidine group were found to greatly increase the affinity of the inhibitor and the enzyme-inhibitor complex half-life. In addition, 5-t-butyl group at the P2 site l-prolyl residue increased the dissociation half-life of the enzyme-inhibitor complex, without much affecting the inhibitory potency. The duration of the inhibition in the rat tissues followed the inhibition kinetic properties in that the compounds with fast dissociation produced shorter inhibition in the rat tissues than the compounds with slow dissociation. The duration of POP inhibition of compounds was evidently not governed by their serum clearance. The fact that the in vivo pharmacodynamic behaviour of POP inhibitors can be predicted by their in vitro-properties may be of importance when designing therapeutically useful POP inhibitors.
authors.affiliation: Department of Pharmacology and Toxicology, University of Kuopio, P.O. Box 1627, Kuopio FI-70211, Finland. Jarkko.Venalainen@uku.fi
authors.forename: Jarkko I
authors.initials: JI
authors.lastname: Venäläinen
authors.forename: J Arturo
authors.initials: JA
authors.lastname: Garcia-Horsman
authors.forename: Markus M
authors.initials: MM
authors.lastname: Forsberg
authors.forename: Aaro
authors.initials: A
authors.lastname: Jalkanen
authors.forename: Erik A A
authors.initials: EA
authors.lastname: Wallén
authors.forename: Elina M
authors.initials: EM
authors.lastname: Jarho
authors.forename: Johannes A M
authors.initials: JA
authors.lastname: Christiaans
authors.forename: Jukka
authors.initials: J
authors.lastname: Gynther
authors.forename: Pekka T
authors.initials: PT
authors.lastname: Männistö
mesh_terms: D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D017931:DNA Primers; D006207:Half-Life; D006801:Humans; D007700:Kinetics; D008297:Male; D000085822:Prolyl Oligopeptidases; D011480:Protease Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D012697:Serine Endopeptidases / Q000187:drug effects*; D013552:Swine
chemical_list: D017931:DNA Primers; D011480:Protease Inhibitors; D012697:Serine Endopeptidases; C000705287:PREPL protein, human; D000085822:Prolyl Oligopeptidases