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
posted on 2023-05-12, 21:34authored byAhmed Fouda, Sarita Negi, Oleg Zaremba, Rita S. Gaidar, Yurii S. Moroz, Eduard Rusanov, Steven Paraskevas, Jean Tchervenkov
Retinoic acid receptor-related orphan receptor γt
(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.