Synthesis of Prolyl Endopeptidase Inhibitors and Evaluation of Their Structure-Activity Relationships: In Vitro Inhibition of Prolyl Endopeptidase from Canine Brain.

Arai, Heihachiro; Nishioka, Hiromi; Niwa, Shigehiko; Yamanaka, Takeshi; Tanaka, Yoshiaki; Yoshinaga, Koji; Kobayashi, Naomi; Miura, Naoyoshi; Ikeda, Yuichi

doi:10.1248/cpb.41.1583

Cited by 33 publications

(32 citation statements)

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“…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%

“…Moreover, a wide variety of cyclic or bicyclic scaffolds are compatible [73][74][75] while open chains can also be fitted. The carbonyl group between this position and the subsequent P1 is crucial for the formation of a hydrogen bond with Arg643 [1], and S stereochemistry is preferred over planar or R stereochemistry [67,76].…”

Section: The Pharmacophore Of Peptidomimetic Inhibitorsmentioning

confidence: 99%

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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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Section: The Pharmacophore Of Peptidomimetic Inhibitorsmentioning

confidence: 99%

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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“…[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%

“…[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. [16,20] The l-prolyl moiety at the P2 site has been very difficult to replace. Only a few successful substitutions that increased potency have been published.…”

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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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Wallén¹,

Christiaans²,

Forsberg³

et al. 2002

J. Med. Chem.

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New dicarboxylic acid bis(L-prolyl-pyrrolidine) amides were synthesized, and their inhibitory activity against prolyl oligopeptidase from pig brain was tested in vitro. As compared with earlier described prolyl oligopeptidase inhibitors, these new compounds have in common an L-prolyl-pyrrolidine moiety, but the typical lipophilic acyl end group is replaced by another L-prolyl-pyrrolidine moiety connected symmetrically with a short dicarboxylic acid linker. These compounds are a new type of peptidomimetic prolyl oligopeptidase inhibitor.

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Synthesis of Prolyl Endopeptidase Inhibitors and Evaluation of Their Structure-Activity Relationships: In Vitro Inhibition of Prolyl Endopeptidase from Canine Brain.

Cited by 33 publications

References 0 publications

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

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

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

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