In Vitro DMPK Assessment and Solubility Evaluation of 2,3-Derivatives of 4,5,6,7-Tetrahydro-benzothiophene Modulators of RORγt
Bibliographic record
Abstract
🧾 AbstractIntroduction: Retinoic acid receptor related orphan receptor gamma t (RORγt) is a nuclear receptor that is expressed in a variety of cell types and is a potential drug target for the treatment of inflammatory and auto-immune diseases, metabolic diseases, and many cancer types. The modulators of RORγt have been clinically tested in autoimmune diseases; however, they showed unacceptable liver and lymphatic tissues toxicity. Lipophilic efficiency, low hepatic clearance, high lymphatic/plasma drug concentration are the major contributing factors. The functional groups that are frequently observed in early RORγt modulators such as CF3-, CF2H- and alkyloxy are among the substructures that are responsible for such unfavorable effects. In addition, most of the RORγt modulators contain 2-4 aromatic rings and logP > 4. Using rational drug design and virtual screening, we discovered a group of 2,3 derivatives of 4,5,6,7 tetrahydro-benzothiophene compounds that inhibit RORγt in TR-FRET, fluorescence polarization binding assays and decrease de novo generation of Th17 cells in human PBMCs. The compounds have good solubility properties. They have diverse microsomal stability and Caco-2 permeability profiles that allow for a wide range of formulation options and organ specific targeting. Objective: to determine the solubility, microsomal stability, and Caco-2 permeability of 2,3 derivatives of 4,5,6,7-tetrahydro benzothiophene modulators of RORγt. Methods: we evaluated the binding of 23 compounds by time resolved fluorescence energy transfer of RORγt-LBD-biotinylated coactivator peptide complex. We additionally performed a competitive binding to full length RORγt against 25-NBD cholesterol. We tested the effect of compounds on Th17 and Treg polarization phenotypic assays. The solubility of 12 compounds was assessed in acidic and neutral pH (1.5, 5 and 7.4). In addition, the microsomal stability was measured in mouse/human/rat/dog and finally Caco-2 permeability was determined. Results: all the compounds tested inhibited RORγt LBD – coactivator binding at nanomolar concentrations (IC50 <100nM) and highly soluble (>200 µM). They showed three clusters in microsomal stability low, moderate, and high intrinsic clearance. Similarly, Caco-2 permeability of the compounds was diverse in range from low, moderate, and high permeability and three compounds undergo active reflux. Conclusion: we identified potent inhibitors of RORγt and can efficiently attenuate Th17 polarization. They can be used in-vivo to block T cells differentiation to Th17 and Tc17 and treat conditions associated with increased IL17 production. The compounds are bioavailable, and they can be developed for organ specific therapies.📁 File DescriptionTwo versions are provided — the initial submission published in the conference proceedings and the final author-approved version, posted online on 22 October 2025.📍 Conference and MetadataPresented at: VIIth International Drug Discovery and Development Forum 2022 Presentation Date: December 8, 2022 Location: Montreal, QC, Canada Abstract Category: Pharmacokinetics and Metabolism Presentation Type: Oral PresentationAuthors: Ahmed Fouda, Sarita Negi, Steven Paraskevas, Jean Tchervenkov Affiliation: Department of Experimental Surgery, McGill University, Montreal, QC, Canada 📚 Full CitationFouda, A.; Negi, S.; Paraskevas, S.; Tchervenkov, J. In-vitro DMPK Assessment and Solubility Evaluation of 2,3-Derivatives of 4,5,6,7-Tetrahydrobenzothiophene Modulators of RORγt. In Proc. Int. Drug Discov. Dev. Forum 2022; 7, 17 (Abstr. 23). VIIth International Drug Discovery and Development Forum, Montreal, QC, Canada, December 8, 2022. DOI: 10.6084/m9.figshare.30422119 © 2022, Ahmed Fouda.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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".