title: New prolyl oligopeptidase inhibitors developed from dicarboxylic acid bis(l-prolyl-pyrrolidine) amides.
abstract: Isophthalic acid bis(l-prolyl-pyrrolidine) amide is a very potent prolyl oligopeptidase inhibitor, but it has a log P value of -0.2, which is very low for a compound targeted to the brain. Therefore, these types of compounds were further modified to improve the structure-activity relationships, with the focus on increasing the log P value. The inhibitory activity against prolyl oligopeptidase from pig brain was tested in vitro. The most promising compounds resulted from replacing the pyrrolidinyl group at the P5 site by cycloalkyl groups, such as cyclopentyl and cyclohexyl groups, and by a phenyl group. These compounds are slightly more potent, and they have a significantly higher log P value. The potency of these compounds was further increased by replacing the pyrrolidinyl group at the P1 site by 2(S)-cyanopyrrolidinyl and 2(S)-(hydroxyacetyl)pyrrolidinyl groups.
authors.affiliation: Department of Pharmaceutical Chemistry, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland. wallen@uku.fi
authors.forename: Erik A A
authors.initials: EA
authors.lastname: Wallén
authors.forename: Johannes A M
authors.initials: JA
authors.lastname: Christiaans
authors.forename: Elina M
authors.initials: EM
authors.lastname: Jarho
authors.forename: Markus M
authors.initials: MM
authors.lastname: Forsberg
authors.forename: Jarkko I
authors.initials: JI
authors.lastname: Venäläinen
authors.forename: Pekka T
authors.initials: PT
authors.lastname: Männistö
authors.forename: Jukka
authors.initials: J
authors.lastname: Gynther
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D011392:Proline / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000085822:Prolyl Oligopeptidases; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D012697:Serine Endopeptidases / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013552:Swine
chemical_list: D007202:Indicators and Reagents; D011480:Protease Inhibitors; D011758:Pyrroles; D011759:Pyrrolidines; C074327:N-(N-(phenyl)butyryl-L-prolyl)pyrrolidine; D011392:Proline; D012697:Serine Endopeptidases; D000085822:Prolyl Oligopeptidases