ml9b00431_si_001.pdf (507.14 kB)
Discovery of N‑(Indazol-3-yl)piperidine-4-carboxylic Acids as RORγt Allosteric Inhibitors for Autoimmune Diseases
journal contributionposted on 2020-01-14, 20:04 authored by 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
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.
Substantial interestTh 17 cellsbenzoic acid moietyanti-IL -17selectivitypharmacokinetic profile4- aza-indazole coreTh 17 pathway modulationoptimizationROR γt inhibitionGM-CSFpiperidinyl carboxylatehormone receptor ROR γtallosteric binding pocketoff-target profilehydroxyl groupAutoimmune Diseasestool compound 14orthosteric bindersROR γt Allosteric Inhibitorsmaster regulator4- F-indazoleROR γt inhibitorspotency-17A-17F