Synthesis and Inhibitory Activity of Acyl-Peptidyl-Pyrrolidine Derivatives Toward Post-Proline Cleaving Enzyme; A Study of Subsite Specificity

Abstract

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.

Benzimidazolium Salts as Small, Nonpeptidic and BBB‐Permeable Human Prolyl Oligopeptidase Inhibitors

“…Another important feature is the low reactivity of benzimidazolium salts when compared with formyl or other previously described covalent inhibitors, which could contribute to decreasing clinical side effects. However, when the potency of our best inhibitors is compared with typical noncovalent reference compounds, such as S-17092-1 (IC 50 value in rat cortical extract: 8.3 nm), [34] SUAM 1221 (IC 50 value in bovine brain extract: 190 nm), [35] it is clear that the potency of these new scaffolds needs to be improved.…”

Low molecular weight inhibitors of Prolyl Oligopeptidase: a review of compounds patented from 2003 to 2010

“…Proline, proline derivatives [58,60,[65][66][67][68][69] or natural a-amino acids, both neutral and charged, are fitted [70][71][72]. Moreover, a wide variety of cyclic or bicyclic scaffolds are compatible [73][74][75] while open chains can also be fitted.…”

Dicarboxylic Acidbis(l-Prolyl-pyrrolidine) Amides as Prolyl Oligopeptidase Inhibitors

“…10 Four reference compounds of this type with different lipophilic acyl end groups are benzoyl-L-prolyl-pyrrolidine, 11 caproyl-Lprolyl-pyrrolidine, 12 SUAM-1221, [11][12][13] and Z-L-prolyl-Lprolinal. 14 SUAM-1221 and Z-L-prolyl-prolinal are the two most potent ones, and the latter has the pyrrolidine group replaced by an L-prolinal group, which increases the activity further.…”