Discovery of N-(Indazol-3-yl)piperidine-4-carboxylic Acids as RORγt Allosteric Inhibitors for Autoimmune Diseases

Abstract

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.

RORγ Structural Plasticity and Druggability

“…We compared the binding modes of nine ligands (Figure 7). Compounds 1-8 were co-crystallized with the LBD [11,[37][38][39][40]. Compound 9 was modeled from MD simulations [41].…”

“…Thus, the pocket is extendable depending on the ligand chemistry. (3) 5C4U [11]; (4) 5C4T [11]; (5) 6UCG [37]; (6) 6TLM [38]; (7) 5LWP [39]; (8) 6SAL [40]. No PDB code is available for compound (9) [41].…”

“…Allosteric inverse agonists binding in the AF-2 site. The corresponding PDB codes for the co-crystal models of the compounds binding in the RORγ LBD are listed as follows: (1) 4YPQ, 5C4O[11]; (2) 5C4S[11]; (3) 5C4U[11]; (4) 5C4T[11]; (5) 6UCG[37]; (6) 6TLM[38]; (7) 5LWP[39]; (8) 6SAL[40]. No PDB code is available for compound (9)[41].…”

RORγ Structural Plasticity and Druggability

“…We compared the binding modes of nine ligands (Figure 7). Compounds 1 -8 were cocrystallized with the LBD [11,[38][39][40][41]. Compound 9 was modeled from MD simulations [42].…”

“…Allosteric inverse agonists binding in the AF-2 site. The corresponding PDB codes for the co-crystal models of the compounds binding in the RORγ LBD are listed as follows:(1) 4YPQ, 5C4O[11]; (2) 5C4S[11]; (3) 5C4U[11]; (4) 5C4T[11]; (5) 6UCG[38]; (6) 6TLM[39]; (7) 5LWP[40]; (8) 6SAL[41]. No PDB code is available for compound 9[42].…”