Potent and Orally Bioavailable Inverse Agonists of RORγt Resulting from Structure-Based Design

Retinoic
acid receptor related orphan receptor γt (RORγt),
has been identified as the master regulator of TH17-cell
function and development, making it an attractive target for the treatment
of autoimmune diseases by a small-molecule approach. Herein, we describe
our investigations on a series of 4-aryl-thienyl acetamides, which
were guided by insights from X-ray cocrystal structures. Efforts in
targeting the cofactor-recruitment site from the 4-aryl group on the
thiophene led to a series of potent binders with nanomolar activity
in a primary human-TH17-cell assay. The observation of
a DMSO molecule binding in a subpocket outside the LBD inspired the
introduction of an acetamide into the benzylic position of these compounds.
Hereby, a hydrogen-bond interaction of the introduced acetamide oxygen
with the backbone amide of Glu379 was established. This greatly enhanced
the cellular activity of previously weakly cell-active compounds.
The best compounds combined potent inhibition of IL-17 release with
favorable PK in rodents, with compound 32 representing
a promising starting point for future investigations.