Design, synthesis and biological evaluation of novel [5,5]-fused thiazolidine/oxazolidine inhibitors for targeting prolyl oligopeptidase
Bibliographic record
Abstract
In the course of developing prolyl oligopeptidase (POP) inhibitors, our group has synthesized different series of inhibitors ranging from chiral bicyclic scaffolds to peptidomimetics, the design of which has been a product of in silico derived high-throughput screening followed by docking-guided optimization. In line with our objective to rigidify a known pseudopeptidic inhibitor, we proposed to develop [5,5]-fused thiazolidine-based inhibitors. This scaffold was previously abandoned due to unforeseen oxidation by cytochrome P450 and subsequent isomerization to yield complex mixtures of metabolites with unknown pharmacodynamic properties. However, the ease of functionalization by which this scaffold could be transformed to mimic the pseudo-peptide and its ideal geometry warranted revisiting. We envision the topology of the bicyclic core can be modified to exhibit either additional steric or electronic constraints, and as such, circumvent our initial dilemma. Herein, we report our findings on an expedited series obtained in fewer than 10 steps, followed by testing in recombinant human POP and living neurons.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".