1 research outputs found
Discovery of N-(Indazol-3-yl)piperidine-4-carboxylic Acids as RORĪ³t Allosteric Inhibitors for Autoimmune Diseases
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 RORĪ³t 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 RORĪ³t inhibition. A variety of RORĪ³t 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 hitĀ 1, a tool compoundĀ 14Ā 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 inĀ 14Ā to 4-F-indazole, and incorporating a key hydroxyl group led to the discovery ofĀ 25, which possesses exquisite potency and selectivity, as well as an improved pharmacokinetic profile suitable for oral dosing.FWN ā Publicaties zonder aanstelling Universiteit Leide