In Vitro DMPK Assessment and Solubility Evaluation of 2,3-Derivatives of 4,5,6,7-Tetrahydro-benzothiophene Modulators of RORγt
Notice bibliographique
Résumé
🧾 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.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».