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

Abstract

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.

Unveiling Prolyl Oligopeptidase Ligand Migration by Comprehensive Computational Techniques

“…POP inhibitors might be valuable compounds in a variety of clinical conditions of the brain, such as the cognitive disturbances present in schizophrenia and bipolar affective disorder, as indicated by their neuroprotective and cognition-enhancing effects in experiments with animals (2). For these reasons, a plethora of POP inhibitors have been developed during the last 10 years for treatment of several central nervous system disorders (3,4). Two basic groups of inhibitors have been proposed: forming a covalent bond with the catalytic serine and noncovalent ones.…”

Parasite Prolyl Oligopeptidases and the Challenge of Designing Chemotherapeuticals for Chagas Disease, Leishmaniasis and African Trypanosomiasis

“…Is the pharmacokinetic of the lead compound appropriate to treat Chagas disease? Interestingly, this last question meets some recent remarks concerning POP inhibitors as therapeutic agents to treat cognitive deficit disorders [109,110]. Although experimental data show that POP inhibitors have neuroprotective activities and the interest in POP inhibitors has been growing for a decade, few inhibitors have progressed into clinical trials.…”

“…Although experimental data show that POP inhibitors have neuroprotective activities and the interest in POP inhibitors has been growing for a decade, few inhibitors have progressed into clinical trials. One reason that has been offered to explain this scenario is, with few exceptions, the lack of studies concerning bioavailability, pharmacodynamics, pharmacokinetics and toxicity of POP inhibitors, as well as the need of an optimal in vivo test model [109]. POPTc80 gene deletion is currently under investigation for evaluating the in vivo virulence potential of mutant parasites.…”

“…The inhibitors obtained with such strategies were moderately selective although parasitic and human POP active sites show structural divergences. POP inhibitors studies are mainly based on the search of new peptidomimetics derived from the reference pharmacophore, but innovative chemical scaffolds based on non-peptide compounds and alkaloids are now emerging (reviewed by [109]). It may be expected that the access to compound libraries covering a large chemical diversity and to high-throughput facilities will be useful to look for new chemical scaffolds showing higher selectivity towards the parasite POP versus the human POP than the classical peptidomimetic approach undertaken until now.…”

Translational research on prolyl oligopeptidase inhibitors: the long road ahead

“…The review entitled 'Low molecular weight inhibitors of Prolyl Oligopeptidase: a review of compounds patented from 2003 to 2010' [1] covers the patents that describe a new wave of inhibitor development and the revival in prolyl oligopeptidase (PREP) research triggered by a report in Nature that reducing PREP expression and administering PREP inhibitors to developing neurons in cell culture counteract some of the effects of lithium (and the mood stabilizing drugs carbamazepine and valproic acid) [2]. In their Expert opinion review, the authors make two observations that merit some reflection.…”