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 gamma;t

摘要

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.