Structure Activity Relationship of Inhibitors Specific for Prolyl Endopeptidase

Yoshimoto, Tadashi; Tsuru, Daisuke; Yamamoto, Nobuto; Ikezawa, Ryuhei; Furukawa, Sunao

doi:10.1080/00021369.1991.10870532

Cited by 8 publications

(7 citation statements)

References 13 publications

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“…One series of substituted dipeptides contained acetals and the other series had no reactive aldehyde group, but contained substitutions on the pyrrolidine ring or an azetidine. Although Yoshimoto reported that introduction of sulphur in the pyrrolidine ring improves inhibition (Yoshimoto et al, 1991), it seems that this is not a general rule, since we found no improvement upon the use of thiazolidine derivatives. Therefore, we followed a different approach for generating an electronic dense region by substitution of hydrogen for fluor on the pyrrolidine ring.…”

Section: Discussioncontrasting

confidence: 47%

Development and Evaluation of Peptide‐Based Prolyl Oligopeptidase Inhibitors — Introduction of N‐Benzyloxycarbonyl‐Prolyl‐3‐Fluoropyrrolidine as a Lead in Inhibitor Design

Goossens

Vanhoof

Meester

et al. 1997

European Journal of Biochemistry

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The current study has been undertaken to develop new and biocompatible inhibitors for prolyl oligopeptidase, a highly specific endopeptidase, proposed to be involved, through its affinity for neuropeptides and kinins, in the processes of learning and memory and in the control of blood pressure. For in vitro evaluation of the inhibitors, human platelet prolyl oligopeptidase was purified to homogeneity and characterized. Northern blot analysis showed that mRNA coding for prolyl oligopeptidase was present in all tissues examined and only one transcript of 3.1 kb was detected. In addition to the human platelet enzyme, we also purified rat brain prolyl oligopeptidase, which proved to have the same characteristics as the human enzyme. In a series of tested peptides, bradykinin was found to be the best substrate. Based on this information, peptides bearing pseudopeptide bonds were generated and evaluated as inhibitors. The experiments clearly demonstrated that changes to the scissile peptide bond significantly decrease the affinity of prolyl oligopeptidase for the peptide derivatives. In our series of synthetic N-terminal blocked dipeptides, N-benzyloxycarbonyl-prolyl-3-fluoropyrrolidine was the most potent compound. Inhibition was reversible, but the inhibitor was bound tightly. Calculation of its K, according to Henderson [Henderson, J. P. (1972) Biochern. J. 127, 321 -3331 yielded a value of 0.8 nM. This compound was not cytotoxic in a cell culture system and inhibited the purified prolyl oligopeptidase from rat as well as from human origin. In vivo evaluation in male Whistar rats showed no acute toxicity. 5 h after administration, the most profound decrease in prolyl oligopeptidase activity was found in the thymus, brain, and testis. This study demonstrates that N-benzyloxycarbonyl-prolyl-3-fluoropyrrolidine is a potent inhibitor and a promising compound suitable to investigate the physiologic function of the enzyme in vitro and in vivo.

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Section: Discussioncontrasting

confidence: 47%

Development and Evaluation of Peptide‐Based Prolyl Oligopeptidase Inhibitors — Introduction of N‐Benzyloxycarbonyl‐Prolyl‐3‐Fluoropyrrolidine as a Lead in Inhibitor Design

Goossens

Vanhoof

Meester

et al. 1997

European Journal of Biochemistry

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“…The first pharmacophore was described by Yoshimoto et al [60], but later SAR studies disclosed new shape features in order to achieve higher selectivity over other prolyl peptidase family proteases, mainly fibroblast activating protein (FAP) and dipeptidyl peptidase IV (DPPIV) [57,61]. In addition, the influence of the electrostatic environment of POP active site in the binding processes was also studied by Szeltner et al [62].…”

Section: The Pharmacophore Of Peptidomimetic Inhibitorsmentioning

confidence: 97%

“…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.…”

Section: The Pharmacophore Of Peptidomimetic Inhibitorsmentioning

confidence: 99%

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

Lopez

Tarragó

Giralt

2011

Expert Opinion on Therapeutic Patents

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The major part of the repertory of POP inhibitors derived from systematical modification of the canonical compound benzyloxycarbonyl-prolyl-prolinal (ZPP). Nevertheless, only two of them have progressed into the clinical trials. One possible reason for this failure is the lack of studies concerning pharmacodynamics, pharmacokinetics and toxicity, together with the absence of suitable animal models. Moreover, POP is still not a well-defined therapeutic target. Further studies are required for the elucidation of the biological role of POP and to validate the therapeutic action of inhibitors in cognitive processes. In contrast, the involvement of POP in protein-protein interactions together with the recent evidences in angiogenesis opens alternative approaches to the traditional active site-directed inhibitors, as well as new therapeutic applications.

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“…[15][16][17] One extensively studied POP inhibitor is Z-l-prolyl-l-prolinal (ZPP), [18] whose crystal structure within the enzyme active site has been published. [19] Enlargement of the pyrrolidine ring or addition of an oxo substituent to the 2-position of the pyrrolidine ring in P1 position decreases the inhibitory activity.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2008

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Prolyl oligopeptidase (POP) is a cytosolic serine peptidase that hydrolyzes proline-containing peptides at the carboxy terminus of proline residues. This peptidase has gained importance as a target for the treatment of cognitive disturbances of patients with neuropsychiatric diseases. Our research addresses the identification of POP inhibitors from a small focused library of polar heterocyclic compounds arising from multicomponent reactions. Two selective POP-specific inhibitors were identified on the basis of their inhibition of dipeptidyl peptidase IV. The most active compounds were evaluated for their in vitro transport through the blood-brain barrier (BBB) using a parallel artificial membrane permeability assay. Our results show for the first time that benzimidazolium salts are new POP-inhibitory scaffolds with properties of solubility, specificity, and lipophilicity that may allow them to cross the BBB by passive diffusion. These findings constitute an excellent starting point to synthesize new POP inhibitors with enhanced properties.

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Structure Activity Relationship of Inhibitors Specific for Prolyl Endopeptidase

Cited by 8 publications

References 13 publications

Development and Evaluation of Peptide‐Based Prolyl Oligopeptidase Inhibitors — Introduction of N‐Benzyloxycarbonyl‐Prolyl‐3‐Fluoropyrrolidine as a Lead in Inhibitor Design

Development and Evaluation of Peptide‐Based Prolyl Oligopeptidase Inhibitors — Introduction of N‐Benzyloxycarbonyl‐Prolyl‐3‐Fluoropyrrolidine as a Lead in Inhibitor Design

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

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

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