Discovery of potent and orally bioavailable inverse agonists of the retinoic acid receptor-related orphan receptor C2

The further optimization of a recently disclosed series of inverse agonists of the nuclear receptor RORC2 is described. Investigations into the left-hand side of compound , guided by X-ray crystal structures, led to the substitution of the 4-aryl-thiophenyl residue with the hexafluoro-2-phenyl-propan-2-ol moiety. This change resulted in to compound , which combined improved drug-like properties with good cell potency and a significantly lower dose, using an early dose to man prediction. Target engagement was demonstrated in the thymus of mice by a reduction in the number of double positive T cells after oral dosing.