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

Retinoic acid receptor-related orphan receptor & gamma;t(ROR & gamma;t)is a nuclear receptor that is expressed in a variety of tissues andis a potential drug target for the treatment of inflammatory and auto-immunediseases, metabolic diseases, and resistant cancer types. We hereinreport the discovery of 2,3 derivatives of 4,5,6,7-tetrahydro-benzothiophenemodulators of ROR & gamma;t. We also report the solubility in acidic/neutralpH, mouse/human/dog/rat microsomal stability, Caco-2, and MDR1-MDCKIIpermeabilities of a set of these derivatives. For this group of modulators,inverse agonism by steric clashes and push-pull mechanismsinduce greater instability to protein conformation compared to agonistlock hydration. Independent of the two mechanisms, we observed a basalmodulatory activity of the tested 2,3 derivatives of 4,5,6,7-tetrahydro-benzothiophenetoward ROR & gamma;t due to the interactions with the Cys320-Glu326and Arg364-Phe377 hydrophilic regions. The drug discovery approachreported in the current study can be employed to discover modulatorsof nuclear receptors and other globular protein targets.

Automated summary

This study discovered 2,3 derivatives of 4,5,6,7-tetrahydro-benzothiophene as potential modulators of RORγt and evaluated their interactions with the protein. The approach used in this study can be applied to discover modulators of nuclear receptors and other globular protein targets.