Synthesis and inhibitory activity of acyl-peptidyl-pyrrolidine derivatives toward post-proline cleaving enzyme; a study of subsite specificity.
Several pyrrolidine derivatives have been synthesized and examined for their inhibitory activity on post-proline cleaving enzymes from Flavobacterium meningosepticum and bovine brain. Almost all the compounds tested in this study inhibited the activity of both enzymes at low IC50 values (from nM to microM) but a specificity difference was observed with alkylacyl-peptidyl-pyrrolidine derivatives which strongly inhibited only the bacterial enzyme. The most effective inhibitors have a proline residue on their P2 sites and a substituted or unsubstituted phenoxybutyryl moiety on their P3 sites. Thus phenoxybutyryl-prolyl-pyrrolidine is the most effective partial structure of the inhibitors. The best inhibitors found were: 4-(4-benzylphenoxy)butyryl-prolyl-pyrrolidine for bacterial enzyme (IC50 1.4 nM) and 4-phenylbutyryl-thioprolyl-pyrrolidine for bovine brain enzyme (IC50 67 nM). In the passive avoidance test, using amnesic rats experimentally induced with scopolamine, the pyrrolidine derivatives which had potent inhibitory activity toward post-proline cleaving enzymes also showed strong anti-amnesic activities at doses of 1-5 mg/kg, i.p.
Saito
M
M
Bio-organic Chemistry Laboratory, Institute for Fundamental Research, Suntory Research Center, Osaka, Japan.
Hashimoto
M
M
Kawaguchi
N
N
Shibata
H
H
Fukami
H
H
Tanaka
T
T
Higuchi
N
N
D000215:Acylation; D000478:Alkylation; D000818:Animals; D001921:Brain / Q000201:enzymology; D002417:Cattle; D005417:Flavobacterium / Q000201:enzymology; D007202:Indicators and Reagents; D007700:Kinetics; D015394:Molecular Structure; D000085822:Prolyl Oligopeptidases; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D012697:Serine Endopeptidases / Q000378:metabolism*; D013329:Structure-Activity Relationship
D007202:Indicators and Reagents; D011480:Protease Inhibitors; D011759:Pyrrolidines; D012697:Serine Endopeptidases; D000085822:Prolyl Oligopeptidases