Discovery of <i>N</i>‑(Indazol-3-yl)piperidine-4-carboxylic Acids as RORγt Allosteric Inhibitors for Autoimmune Diseases Hongjun 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 10.1021/acsmedchemlett.9b00431.s001 https://acs.figshare.com/articles/journal_contribution/Discovery_of_i_N_i_Indazol-3-yl_piperidine-4-carboxylic_Acids_as_ROR_t_Allosteric_Inhibitors_for_Autoimmune_Diseases/11607417 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 <b>1</b>, a tool compound <b>14</b> 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 <b>14</b> to 4-F-indazole, and incorporating a key hydroxyl group led to the discovery of <b>25</b>, which possesses exquisite potency and selectivity, as well as an improved pharmacokinetic profile suitable for oral dosing. 2020-01-14 20:04:24 Substantial interest Th 17 cells benzoic acid moiety anti-IL -17 selectivity pharmacokinetic profile 4- aza-indazole core Th 17 pathway modulation optimization ROR γt inhibition GM-CSF piperidinyl carboxylate hormone receptor ROR γt allosteric binding pocket off-target profile hydroxyl group Autoimmune Diseases tool compound 14 orthosteric binders ROR γt Allosteric Inhibitors master regulator 4- F-indazole ROR γt inhibitors potency -17A -17F