Dicarboxylic acid azacycle l-prolyl-pyrrolidine amides as prolyl oligopeptidase inhibitors and three-dimensional quantitative structure-activity relationship of the enzyme-inhibitor interactions.
A series of dicarboxylic acid azacycle l-prolyl-pyrrolidine amides was synthesized, and their inhibitory activity against prolyl oligopeptidase (POP) from porcine brain was tested. Three different azacycles were tested at the position beyond P3 and six different dicarboxylic acids at the P3 position. l-Prolyl-pyrrolidine and l-prolyl-2(S)-cyanopyrrolidine were used at the P2-P1 positions. The IC(50) values ranged from 0.39 to 19000 nM. The most potent inhibitor was the 3,3-dimethylglutaric acid azepane l-prolyl-2(S)-cyanopyrrolidine amide. Molecular docking (GOLD) was used to analyze binding interactions between different POP inhibitors of this type and the POP enzyme. The data set consisted of the novel inhibitors, inhibitors published previously by our group, and well-known reference compounds. The alignments were further analyzed using comparative molecular similarity indices analysis. The binding of the inhibitors was consistent at the P1-P3 positions. Beyond the P3 position, two different binding modes were found, one that favors lipophilic structures and one that favors nonhydrophobic structures.
Jarho
Elina M
EM
Department of Pharmaceutical Chemistry, P.O. Box 1627, FI-70211 Kuopio, Finland. Elina.Jarho@uku.fi
Wallén
Erik A A
EA
Christiaans
Johannes A M
JA
Forsberg
Markus M
MM
Venäläinen
Jarkko I
JI
Männistö
Pekka T
PT
Gynther
Jukka
J
Poso
Antti
A
D000577:Amides / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D003998:Dicarboxylic Acids / Q000138:chemical synthesis / Q000494:pharmacology; D066298:In Vitro Techniques; D008958:Models, Molecular; D011392:Proline / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D000085822:Prolyl Oligopeptidases; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013552:Swine
D000577:Amides; D001372:Aza Compounds; D003998:Dicarboxylic Acids; D011759:Pyrrolidines; D015842:Serine Proteinase Inhibitors; D011392:Proline; D012697:Serine Endopeptidases; D000085822:Prolyl Oligopeptidases