posted on 2020-01-14, 20:04authored byHongjun Zhang, Blair T. Lapointe, Neville Anthony, Rita Azevedo, Jos Cals, Craig C. Correll, Matthew Daniels, Sujal Deshmukh, Hans van Eenenaam, Heidi Ferguson, Laxminarayan G. Hegde, Willem Jan Karstens, John Maclean, J. Richard Miller, Lily Y. Moy, Vladimir Simov, Sunil Nagpal, Arthur Oubrie, Rachel L. Palte, Gopal Parthasarathy, Nunzio Sciammetta, Mario van der Stelt, Janice D. Woodhouse, B. Wesley Trotter, Kenneth Barr
The
clinical success of anti-IL-17 monoclonal antibodies (i.e.,
Cosentyx and Taltz) has validated Th17 pathway modulation for the
treatment of autoimmune diseases. The nuclear hormone receptor RORγt
is a master regulator of Th17 cells and affects the production of
a host of cytokines, including IL-17A, IL-17F, IL-22, IL-26, and GM-CSF.
Substantial interest has been spurred across both academia and industry
to seek small molecules suitable for RORγt inhibition. A variety
of RORγt inhibitors have been reported in the past few years,
the majority of which are orthosteric binders. Here we disclose the
discovery and optimization of a class of inhibitors, which bind differently
to an allosteric binding pocket. Starting from a weakly active hit 1, a tool compound 14 was quickly identified
that demonstrated superior potency, selectivity, and off-target profile.
Further optimization focused on improving metabolic stability. Replacing
the benzoic acid moiety with piperidinyl carboxylate, modifying the
4-aza-indazole core in 14 to 4-F-indazole, and incorporating
a key hydroxyl group led to the discovery of 25, which
possesses exquisite potency and selectivity, as well as an improved
pharmacokinetic profile suitable for oral dosing.