Discovery, Synthesis, and In Vitro Characterization of 2,3 Derivatives of 4,5,6,7-Tetrahydro-Benzothiophene as Potent Modulators of Retinoic Acid Receptor-Related Orphan Receptor γt.
Ahmed FoudaSarita NegiOleg ZarembaRita S GaidarYurii S MorozEduard RusanovSteven ParaskevasJean TchervenkovPublished in: Journal of medicinal chemistry (2023)
Retinoic acid receptor-related orphan receptor γ t (RORγt) is a nuclear receptor that is expressed in a variety of tissues and is a potential drug target for the treatment of inflammatory and auto-immune diseases, metabolic diseases, and resistant cancer types. We herein report the discovery of 2,3 derivatives of 4,5,6,7-tetrahydro-benzothiophene modulators of RORγt. We also report the solubility in acidic/neutral pH, mouse/human/dog/rat microsomal stability, Caco-2, and MDR1-MDCKII permeabilities of a set of these derivatives. For this group of modulators, inverse agonism by steric clashes and push-pull mechanisms induce greater instability to protein conformation compared to agonist lock hydration. Independent of the two mechanisms, we observed a basal modulatory activity of the tested 2,3 derivatives of 4,5,6,7-tetrahydro-benzothiophene toward RORγt due to the interactions with the Cys320-Glu326 and Arg364-Phe377 hydrophilic regions. The drug discovery approach reported in the current study can be employed to discover modulators of nuclear receptors and other globular protein targets.
Keyphrases
- small molecule
- drug discovery
- binding protein
- protein protein
- endothelial cells
- oxidative stress
- emergency department
- risk assessment
- squamous cell carcinoma
- climate change
- molecular dynamics simulations
- lymph node metastasis
- replacement therapy
- structure activity relationship
- crystal structure
- simultaneous determination