Combating Autoimmune Diseases With Retinoic Acid Receptor

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Combating Autoimmune Diseases With Retinoic Acid ReceptorRelated Orphan Receptor-# (ROR# or RORc) Inhibitors: Hits and Misses Vrajesh Bhaskarbhai Pandya, Sanjay Kumar, Sachchidanand Sachchidanand, Rajiv Sharma, and Ranjit C Desai J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jmedchem.8b00588 • Publication Date (Web): 16 Jul 2018 Downloaded from http://pubs.acs.org on July 17, 2018

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Journal of Medicinal Chemistry

Title Combating Autoimmune Diseases With Retinoic Acid Receptor-Related Orphan Receptor-γ (RORγ or RORc) Inhibitors: Hits and Misses

Author Information Vrajesh B. Pandya*, Sanjay Kumar, Sachchidanand, Rajiv Sharma, and Ranjit C. Desai Zydus Research Centre, Cadila Healthcare Limited, Sarkhej Bavla NH8A, Moraiya, Ahmedabad 382210 India

ABSTRACT The nuclear receptor retinoic acid receptor-related orphan receptor gamma (RORγ or RORc) is a key transcription factor for the production of pro-inflammatory cytokines implicated in the pathogenesis of autoimmune diseases. Recently, small molecule inhibitors of RORc drew the enormous attention of the research community worldwide, as a possible therapy for autoimmune diseases, mediated by the IL-17 cytokine. With the clinical proof-of-concept inferred from a small molecule inhibitor VTP-43742 for psoriasis and recent inflow of several RORc inhibitors into the clinic for therapeutic interventions in autoimmune diseases, this field continues to evolve. This review briefly summarizes the RORc inhibitors disclosed in the literature and discusses the progress made by these inhibitors in combating autoimmune diseases.

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INTRODUCTION Autoimmune diseases represent chronic inflammatory conditions that occur as a consequence of genetic susceptibility, environmental factors, and immune dysregulation. The immune system is a highly regulated defense mechanism capable of differentiating the “good” and “bad” substances encountered in the body. The breakdown of this system as a result of the destruction of body’s own cells leads to “autoimmunity” defined as a disturbance in the process of antigenic recognition and elimination.1 The imbalance of protective immune responses and overexpression of the pro-inflammatory cytokines triggers autoimmune diseases and are one of the leading causes of morbidity and mortality worldwide. Autoimmune diseases may localize to a particular organ, e.g., type 1 diabetes, inflammatory bowel diseases (IBD), multiple sclerosis (MS), uveitis, and psoriasis. However, other autoimmune diseases such as rheumatoid arthritis (RA), ankylosing spondylitis (AS), Behcet’s disease, and systemic lupus erythematosus have systemic manifestation. The pro-inflammatory cytokines interleukin-17 (IL-17) and IL-23 have received substantial attention over the last decade for their involvement in the autoimmune inflammatory diseases, and are currently being targeted by several biologics in the clinic.2,3 The antibodies directed against IL-17 (e.g., Secukinumab, Ixekizumab) and IL-17 receptor (e.g., Brodalumab) have recently demonstrated clinical efficacy in psoriasis, RA, and uveitis (Figure 1).3 The IL-23 antibodies such as Ustekinumab, Briakinumab, Tildrakizumab, and Guselkumab have also been evaluated clinically demonstrating efficacy in several autoimmune disorders, especially in psoriasis (Figure 1).2 The antibodies against both IL-17 and IL-23 have now established roles in psoriasis. However, in Crohn’s disease, IL-17 antibodies further worsen the disease, unlike IL-23 antibody’s attenuating effect by decreasing colonic inflammation, and increasing regulatory T cell (Treg) accumulation. Significant weakening of the intestinal epithelial barrier and increased


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colonic inflammation in a murine colitis model occurred following IL-17A or IL-17A receptor inhibition. Based on this it appears that IL-17A acts on the intestinal epithelium to promote barrier function and partly explains the mechanisms underlying exacerbation of Crohn’s disease by IL-17 antibodies.4 Cytokines IL-17 (IL-17A and IL-17F), IL-21, IL-22, and granulocyte-macrophage colony stimulating factor (GM-CSF) are produced by a subset of T-cells called Th17 cells differentiated from naïve CD4+T cells. The differentiation process requires the presence of cytokines IL-6 and transforming growth factor (TGF)-β, while cytokine IL-23 assists in amplification and stabilization of these cells (Figure 1). The nuclear receptor (NR) retinoic acid receptor-related orphan receptor gamma (RORγ, murine form or RORc, human form) is a key transcriptional factor for the differentiation of Th17 cells. This was evident by comparing wild-type and RORγ null mice for the development of Th17 cells.5 RORγ signature genes have been characterized in both mouse and human Th17 cells.6,7 In addition to Th17 cells, RORγ controls the production of these cytokines from other immune cells including Th1/17 cells, CD8+ Tc17 cells, natural killer T cells, innate lymphoid cells (ILC), and γ/δ T cells. RORγ inhibition, therefore, provides a strategy to control proinflammatory cytokines produced by Th17 cells. In fact, it has now become a very important therapeutic target for the small molecule inhibitors that affect IL-17 production (Figure 1).8 In addition to RORγ, ROR family has two more members, RORα and RORβ encoded by separate genes and are homologous. RORα is widely expressed in many tissues, including testis, kidney, adipose, liver, and brain, while RORβ is expressed in brain and retina.9 The mice lacking RORα and RORβ are characterized by severe ataxia and motor defects, respectively.9 RORγ and its splice variant RORγt (shortened by 24 amino acids at N-terminal) have a distinct expression,



while RORγ is present in liver, adipose tissue, skeletal muscle, and kidney, RORγt is present only in the thymus.9 RORγt-deficient mice show significantly decreased susceptibility to experimental autoimmune encephalomyelitis (EAE) as well as the intestinal and skin inflammation.10 Furthermore, mice deficient in RORγ exhibited improved insulin sensitivity and glucose tolerance.11 However, mice deficient in RORγ expression lack lymph nodes and Peyer's patches.12 The lack of these lymphoid structures is the outcome of the absence of lymphoid tissue inducer (LTi) cells in RORγt-deficient mice, as RORγt is required for the differentiation of LTi cells.13 Thymic tissue in RORγ−/− mice had fewer thymocytes when compared with wild-type animals due to the massive apoptosis of double negative thymocytes.14 RORγt+/- mice with enhanced green fluorescent protein gene heterozygously knocked-in at the RORγt gene locus showed increase mortality after myocardial infarction (MI).15 This result suggests a cardioprotective role of the RORγt-expressing cells in cardiac remodeling after MI. The structure of RORγ is modular and has a variable N-terminal activation function (AF-1) domain, a highly conserved central DNA binding domain (DBD), a flexible hinge region and a C-terminal ligand binding domain (LBD) with the ligand-dependent activation function helix 2 (AF-2).9 It is the LBD where the entire focus of discovery and design of small molecule modulators is directed. Multiple structures of LBD in apo- and holo-NRs (with an agonist or inverse agonist occupying the ligand binding pocket (LBP)) have been studied with peptides from coregulatory proteins bound to its surface. A typical NR LBD consists of 12 α-helices (H1H12) organized in three layers, with two or three β-strands forming a short sheet structure. The LBP is mainly hydrophobic where ligands interact with the receptor through extensive van der Waals contacts and few polar interactions. The ligand-bound LBP is packed against H12 on one side and H5 on the other side.


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One of the X-ray crystal structure of RORc agonist, 25-hydroxycholesterol, bound to the LBD of RORc (PDB: 3L0L) was shown to have mainly hydrophobic LBP with some polar residues Arg364, Arg367, Gln286, His479, and Tyr502 lining the LBP.16 The RORc-LBD comprises the 12 α-helices (H1−H12) along with three β-strands. The LBD interacts with the coregulators to regulate gene transcription. The coregulators bind to LBD using one or more LXXLL motifs and associate with H12 via a charge clamp (supporting this motif’s binding as a short α-helix) to the surface of the LBD. Activation by a coactivator complex in RORc is believed to involve the movement of H12 (AF-2) into a hydrophobic pocket of the LBD.9 25hydroxycholesterol indirectly stabilizes the agonist position of Tyr502 (on H12) via a watermediated hydrogen bond, while 25-hydroxy group makes a direct hydrogen bond with the His479 on H11.16 Comparison of multiple cocrystal structures of RORc with agonists and inverse agonists has highlighted the important structural features associated with the active and inactive conformation of RORc. Therefore, agonist and inverse agonist of RORc may be defined with respect to conformational changes it caused. An agonist of RORc is any molecule that enhances the interactions of LBD with one or more coactivator LXXLL motifs (leading to transcriptional activation). The hydrogen bond between His479 (on H11) and Tyr502 (on H12) has been shown to be critical for RORγ agonist activity. An inverse agonist is any molecule, which position H12 to physically compete with and block the site of coactivators, or stabilizes the inactive conformation of RORc. In other words, upon binding of an inverse agonist, the interaction of the LBD with the coactivator will change as H12 would have perturbed conformation and position relative to the LBD core; abrogating the interaction with either a coactivator or a corepressor.



A recent publication by Novartis scientists proposed a new molecular mechanism to explain inverse agonism in RORc, where an inverse agonist is cocrystallized with a coactivator peptide and H12 in agonist position.17 It proposes that H12 is destabilized by a gain of free energy upon liberation of an unstable water molecule (trapped in a partially hydrophobic environment interacting with Tyr502) into bulk solvent. It was named as “water trapping” mechanism. The process of identifying small molecule RORc inhibitors has made significant progress with several small molecules entering into the clinic, including VTP-43742 (Phase II, Vitae/Allergan),18 GSK-2981278 (Phase II, GSK),19 ARN-6039 (Phase I, Arrien),20 TAK-828 (Phase I, Takeda),21 ABBV-553 (Phase I, AbbVie),22 JNJ-3534 (Phase I, Janssen/Phenex),23 AZD-0284 (Phase I, AstraZeneca),24 JTE-451 (Phase I, Japan Tobacco/Orphagen),25 JTE-151 (Phase I, Japan Tobacco),26 and RTA-1701 (Phase I, Reata)27 again reemphasizing the emerging role of RORc inhibitors in autoimmune disorders.8,28,29,30 A recent review summarized the discovery and development of RORc agonists as a potential small molecule therapeutics for cancer.31 Structural classes of many of these agonists are overlapping with those described for RORc inverse agonists.8,28,29,30 The scope of the present review is limited to the RORc inhibitors and their role in autoimmune diseases. RORc INHIBITORS The journey of RORc inhibitors can be credited to the discovery of the compound 1 (T0901317), reported initially by Tularik as a potent liver X receptor (LXR) agonist and later as a RORc inverse agonist by Scripps Florida (Figure 2).32 The team at Scripps Florida showed compound 1 as a dual inverse agonist of RORc (IC50 = 1.7 µM) and RORα (IC50 = 2.0 µM) in GAL4-LBD assays. Further efforts led to the discovery of SR2211 (2, GAL4 IC50 = 0.32 µM)33 and SR1555 (3, GAL4 IC50 = 1.5 µM)34 as selective RORc inhibitors devoid of LXR liability and efficacious


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in collagen-induced arthritis (CIA) mouse model (Figure 2).35 Furthermore, Genentech reported a 2.9 Å X-ray cocrystal structure of 1 with RORc-LBD (PDB: 4NB6) where it mainly occupies the hydrophobic pocket.36 In contrast with LXR, the hexafluoroisopropanol group of 1 does not make any strong hydrogen bond to the protein. The phenyl-sulfonamide group of 1 was involved in a π–π stacking interaction with Phe367 in RORc-LBD. Interestingly, another cocrystal structure of 1 with RORγt [264-499, devoid of helix 12] construct at 2.26 Å revealed that the OH group of 1 makes a strong hydrogen bond with His479 (PDB: 5NTQ).17 This difference was attributed to the use of different RORγt construct ([262-507] in 4NB6 vs. [264-499] in 5NTQ) or different resolutions. Last five years have witnessed a great acceleration in identifying potent and selective RORc inhibitors derived from a variety of scaffolds. There are 68 crystal structures of RORc deposited in the protein data bank (PDB). Based on the similarity in their binding interactions with RORc and the chemotype resemblance of the inhibitors, we have classified them into six types as follows. (1)

Sulfonamides of cyclic amines The high throughput screening (HTS) campaign at Bristol-Myers Squibb and subsequent

structure-activity relationship (SAR) investigation led to the series of sulfonamide derivatives (46, Figure 3).37 The X-ray cocrystal structure of 4 bound to LBD of RORγt at 2.40 Å (PDB: 6BN6) revealed destabilization of helix 12. The hexafluoroisopropanol group occupies a hydrophobic pocket and the hydroxyl moiety forms a hydrogen bond with the side chain of His479. One of the sulfone oxygen atoms forms a hydrogen bond with the side chain of Cys320. The tetrahedral sulfone group is crucial since it projects the 4-fluorophenyl moiety to have favorable hydrophobic interaction. The sulfone group, when replaced with a carbonyl (not



shown) afforded a compound with poor activity. The hydroxyl group of 2-hydroxy-2methylpropyl acetamide moiety forms water-mediated hydrogen bonds to the side chain of Arg367 and the backbone carbonyl of Arg364. These interactions are crucial for RORγt potency and selectivity against LXRβ. The poor selectivity of compound 4 (RORγt EC50 = 12 nM in GAL4 assay) against Pregnane X Receptor (PXR) (PXR EC50 = 144 nM in transactivation assay using HepG2 cells) was addressed by moving acetamide side chain of 4 adjacent to nitrogen atom of the ring (e.g., 5, EC50 = 15 nM (RORγt), 1830 nM (PXR)). The most optimized compound 6 (EC50 = 39 nM (RORγt), 2000 nM (PXR)) was identified by introducing fluoro atom on 5 to increase metabolic stability in mice. To evaluate in vivo efficacy, IL-17 mouse model of efficacy was developed. Naive mice were challenged three times with IL-2 and IL-23 (at 0, 7, and 23 h) after IL-2 alone priming (-24 h). Serum IL-17 was measured 7 h after last IL2/IL-23 administration. Oral dosing of compound 6 inhibited IL-17 response by 74% and 98% at 25 mg/kg and 100 mg/kg doses, respectively. The HTS campaign and subsequent SAR study at Genentech resulted in the identification of tetrahydroquinoline derivatives substituted with a carboxamide group (e.g., 7, Figure 3).38 Compound 7 was shown to inhibit recruitment of the SRC1 coactivator peptide to the RORcLBD with an EC50 value of 26 nM. In the RORc binding assay, it has shown the IC50 value of 50 nM and displayed 63-fold selectivity over the other ROR isoforms and 13-fold selectivity over the other NRs in the cell assay panel. Further, it inhibited IL-17 production in the human peripheral blood mononuclear cell (PBMC) assay with an EC50 value of 1400 nM. A molecular modeling study of 7 suggested a very similar binding mode as that of 1 (PDB: 4NB6). The benzamide group in 7 projected toward the C-terminus of the helix 11 in a similar vector as the hexafluoroisopropanol group in 1.


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HTS campaign at AstraZeneca resulted in the identification of benzoxazepine carboxamides (e.g., 8, Figure 3) as RORγ inverse agonists.39 The SAR studies were directed to improve potency and physiochemical properties of their earlier hits. The optimized compound 8 was shown to bind with RORγ-LBD in SPA (scintillation proximity assay) with an IC50 value of 0.04 µM. In the TR-FRET assay, despite having an IC50 value of 0.04 µM, the % efficacy was only 69, suggesting a partial inverse agonist nature of this compound. The ortho-substituted halogens and presence of carboxamide group and its point of attachment had a significant effect in improving potency. Compound 8 inhibited IL-17 production from human Th17 cells with an IC50 value of 0.18 µM (-73% efficacy). The corresponding benzazepine derivative of 8 displayed comparable activity (i.e., 9, IC50 = 0.02 µM (SPA), 0.03 µM (TR-FRET)) in biochemical assays. In IL-17 production assay, 9 had an improved activity (IC50 = 0.04 µM (9) vs. 0.18 µM (8)). Both the compounds were found to be selective against ROR isoforms and related NRs, however, they suffered from low metabolic stability in human liver microsomes (HLM). The cocrystallization of 8 with the RORγ-LBD (native construct, PDB: 5APK) revealed the hydrogen bond of His479 with the NH of the benzamide moiety, disrupting the His-Tyr agonist lock. Also, an induced fit was observed around benzamide moiety in a pocket formed by the key residues from the helix 11.39 The chemotypes described in this section were also explored by many researchers to identify RORc agonists with trivial modifications.31 (2)

Acyclic Sulfonamides and Sultam derivatives Biochemical screening campaign at Genentech identified a series of tertiary sulfonamides

and sultam derivatives (e.g., 10-13, Figure 4) as RORc modulators.40 The piperazine derivative 10 was shown to inhibit RORc with EC50 values of 57 nM and 120 nM in RORc-SRC1 and GAL4 assays, respectively. A publication from Genentech described the reversal of biological



activity regarding agonist/inverse agonist on minor variation in the structure.41 In a RORc-LBD recruitment assay using SRC1 coactivator peptide, 11 having a benzyl group was found to be an inverse agonist (EC50 = 11 nM, −99% efficacy), while the corresponding phenyl analog 12 revealed agonistic behaviour (EC50 = 69 nM, +35% efficacy). Further confirmation was achieved using a human IL-17 PBMC assay where inverse agonist 11 has shown decreased production of IL-17 (EC50 = 0.35 µM, −79% efficacy) and agonist 12 has shown increased production of IL-17 (EC50 = 0.78 µM, +77% efficacy). The binding mode of these compounds was studied by solving cocrystal structures of inverse agonist 10 (close analog of 11, PDB: 4WQP) and agonist 12 (PDB: 4WPF) with RORc-LBD (Figure 5).41 The agonist ligand 12 stabilizes the agonist conformation of helix 12 by aligning itself against Trp317, His479, and Tyr502, and recruited the coactivator peptide. On the other hand, the benzyl moiety of the inverse agonist ligand 10 prevented the formation of the hydrogen bond with Tyr502 of helix 12 through displacement of His479. The disruption of the hydrogen bond between His479 and Tyr502 dislodged helix 12 entirely in the costructure with 10. This prevents the binding site for coregulator proteins and imparts an inverse agonist activity (Figure 5). Both 10 and 12 formed a water-mediated hydrogen bond with Arg367 through the terminal acetyl groups. One of the sulfonamide oxygen atoms forms a hydrogen bond with His479 while remaining interactions were mostly hydrophobic in nature. Further efforts to address metabolic stability issues in compounds (10-12) were reported as conformationally restricted sultam derivatives (e.g., 13, Figure 4), mainly to prevent metabolism in the form of N-dealkylation.42 Compound 11 discussed above has been shown to suffer from the low metabolic stability in liver microsomes of both human (HLM) and rat (RLM) species (CLhep (mL/min/kg): 19 (HLM) and 50 (RLM)). The sultam derivative 13 (RORc SRC1 EC50 =


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12 nM) has shown improved metabolic stability (CLhep (mL/min/kg): 10 (HLM), 21 (RLM)) and also improved rat pharmacokinetic (PK) properties (F(%) = 55, T½ = 3.5 h).42 The Rstereochemistry of the phenyl ring was found to be crucial for the in vitro potency and improved metabolic stability. Furthermore, compound 13 was shown to reduce homodimeric IL-17FF levels by 54% when dosed orally at 30 mg/kg in mice pretreated with a pan-CYP inhibitor (1aminobenzotriazole) and subsequent stimulation with IL-1β and IL-23.42 In their previous patent publication, the SAR around N-acetyl piperazine group, which is involved in a hydrogenbonding with the Arg367 residue of RORc-LBD was described.43 Few potential bioisosteric replacements of N-acetyl piperazine group disclosed in it are shown in the box (Figure 4). A team from GSK disclosed reverse sulfonamide derivatives exemplified by 14 (GSK2981278, Figure 4) as RORγ inverse agonist.44 It was shown to inhibit SRC1 coactivator recruitment and IL-17 production in hPBMCs with IC50 values of 20 nM and 63 nM, respectively.45 The tetrahydropyran group as discussed above may serve as a hydrogen bond acceptor group for Arg367 residue interaction (see box, Figure 4). Compound 14 is their clinical candidate being evaluated for the topical treatment of psoriasis. The in vivo efficacy of 14 was demonstrated in the mouse model of psoriasis.46 Mice were treated topically with 14 (1% ointment) for 13 days (day -3 to day +9). Starting on day 0, mice were challenged topically with 5% imiquimod (IMQ) cream for up to ten days (day 0 to day +9). On the last day of treatment, the skin was imaged and clinically assessed. Mice treated with 14 exhibited a reduced skin redness, scaling, and decreased hyperplasia, which was evident from a 23% reduction in epidermal thickness when compared to the placebo+IMQ-treated group.46 The ex vivo efficacy was also demonstrated in the diseased human skin in which compound treatment reduced levels



of IL-17A, IL-17F, IL-22, and IL-19 transcript levels by > 50% compared to vehicle-treated psoriatic explants.46 A recent publication by Galderma/Nestlé disclosed preclinical characterization of 15 (CD12681), a structurally related RORγ inverse agonist to 14 for the topical treatment of psoriasis (Figure 4).47 In RORγ GAL4 cellular assay, 15 displayed an IC50 value of 19 nM and found to be selective against related NRs. Compound 15 was topically applied (3% w/w in acetone) twice a daily for 16 days in a mouse model of IL-23-induced skin inflammation. Significant reduction in ear thickness and IL-17 inflammatory cell recruitment was observed for 15. (3)

Aryl sulfonyl compounds Compounds of this type possess characteristic sulfonyl group attached to aryl/heteroaryl ring

and involved in key hydrogen bond interactions contributing to high RORc inhibitory potency (Figure 6). The HTS campaign at GSK followed by initial SAR led to the identification of aminothiazole derivative 16, a partial agonist (RORγt FRET IC50 = 160 nM, 56% inhibition) for which cocrystal structure with RORγt-LBD was reported (PDB: 4XT9).48 The signature group (i.e., sulfonyl) was involved in hydrogen-bonding interactions with Arg367 and backbone NH of Leu287. The NH from linker amide of ligand formed a hydrogen bond with the backbone carbonyl of Phe377. Two ligand phenyl rings are in π–π stacking with Phe377 and Phe388. The phenyl group at 5-position of the thiazole ring occupies the hydrophobic pocket contributing to the activation of RORγt by stabilizing the H12 (AF-2 domain) toward SRC recruitment. However, compound 17 (Figure 6) with a carbonyl spacer was found to be an inverse agonist (FRET IC50 = 16 nM, IL-17 IC50 = 200 nM).49 The X-ray structure of 17 with RORγt [264-518] construct and RIP140 coactivator peptide at 1.85 Å (PDB: 5NU1) revealed a trapped water molecule that forms hydrogen bonds with Tyr502 and His479.17 This may lead to the


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destabilization of helix 12 by gain of free energy upon liberation of a water molecule into the bulk solvent (“water trapping” mechanism), explaining the inverse agonist nature of this ligand. Furthermore, in vivo efficacy was demonstrated in the mouse EAE and CIA models upon oral dosing at 100 mg/kg bid.49 Compound 17 was independently evaluated by Phenex and found to be a potent inhibitor of RORβ (FRET IC50 = 79 nM).50 Additional efforts by researchers of GSK to improve central nervous system (CNS) penetrability by removing carbonyl group of 17 led to the series of biaryl amides exemplified by 18 and 19 (Figure 6).51 Compounds 18 (GSK805) and its methyl analogue 19 showed an excellent in vitro potency in RORγ FRET (IC50 = 4 nM (18), 5 nM (19)) and a Th17 cell differentiation (IC50 = < 6.3 nM (18), 40 nM (19)) assays. The CNS permeability was impressive as reflected in their brain-to-blood ratio (0.78 (18), 0.79 (19)). Compound 19 displayed an excellent PK profile (F(%) = 100, T1/2 = 9.7 h) in mouse. Furthermore, both the compounds were found to be efficacious in a mouse model of EAE with the highest effect observed at 10 mg/kg po.51,52 In a very recent publication by GSK, compound 20 (Figure 6) has been shown as a long inverse agonist that dispels both a corepressor peptide (NCOR2) and a coactivator peptide (SRC1) in a dual FRET assay.53 The short inverse agonist (e.g., a close analog of 18), on the other hand, dispels a coactivator peptide only. Compound 20 was shown to have an IC50 value of ~31 nM in both RORγ FRET and RORγ dual FRET assays. This difference in the mechanism of action needs further attention to derive additional insights into the new design of the RORc inhibitors. Our group recently identified cyclopropyl derivatives exemplified by 21 (Figure 6) as potent RORγt inhibitors.54 The unique 1,1-disubstituted cyclopropyl ring may project aryl/heteroaryl rings attached with it for the better occupancy in the hydrophobic pocket of RORγt-LBD.



Compound 21 inhibited RORγt with an IC50 value of 2.1 nM in luciferase assay and also IL-17 production in human PBMC cells (IC50 = 6.6 nM). Furthermore, undisclosed compounds of the invention have demonstrated excellent in vivo efficacy in three disease models in mouse, including EAE model of MS (> 90% reduction in the clinical score at 50 mg/kg bid, po), CIA model of RA (75% reduction in the clinical score at 30 mg/kg bid, po), and IMQ-induced psoriasis model (40% reduction in ear weight at 3 mg/kg bid, po). The compound 22 (VTP-43742, Figure 6) was evaluated by Vitae in Phase II clinical trial for psoriasis.55 In preclinical studies, 22 was shown as a potent inhibitor of RORγ in both the binding assay (RORγ IC50 = 3.7 nM) and a cell-based assay (RORγt IC50 = 17 nM) with more than 1000-fold selectivity against other ROR isoforms.56 It potently inhibits the secretion of IL17A from activated human PBMCs (IC50 = 21 nM) and human whole blood from healthy (IC50 = 207 nM) and psoriatic donors (IC50 = 250 nM). The PK profile in rat (F(%) = 64, T½ = 6 h) and dog (F(%) = 66, T½ = 15 h) was shown as favorable to go for once-daily dosing in humans. In mouse EAE model, at 15 mg/kg (twice daily) oral dosage, a decrease in clinical score and suppression of inflammatory markers in the spinal cord was observed. At 100 mg/kg (twice daily) oral dosage, the compound completely suppressed the EAE clinical score (> 95%), while the corresponding effect of anti-IL-17A mABs was at ~60% reduction in clinical score.56 The Xray structure of 22 with RORγt [264-518] construct and RIP140 coactivator peptide revealed that the terminal CF3 group makes close contacts with His479 and Trp317 leading to the destabilization of helix 12 in agonist position (PDB: 5NTW).17 However, further cocrystallization with RIP140 was possible, and also there was a water molecule trapped making a hydrogen bond with Tyr502. Hence, it appears that 22 works by a combination of mechanisms (i.e., both by the steric clash with helix 12 and “water trapping”).17 In a follow-up patent from


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Vitae, 22 was shown to inhibit hERG by 45.4% at 3 µM, however, no cardiac abnormalities were reported for this compound.57 The same application described compound 23 (RORγ Ki = < 100 nM in the binding assay) with improved hERG profile (7.7% inhibition at 3 µM) and also improved potency (IC50 < 100 nM) in human whole blood assay. This effect may be assigned to a polar hydroxymethyl group. An additional feature in compounds 22 and 23 is the inverted connectivity of the carboxamide group to the central core unlike compounds 18-21 described earlier. A team from Glenmark disclosed a series of ether derivatives exemplified by 24 (RORc TRFRET IC50 = 4.3 nM) for their intended use in respiratory indications (Figure 6).58 Intranasal delivery of compound 24 has demonstrated a significant inhibition of pulmonary inflammation and emphysema induced by cigarette smoke in male C57/BL6 mice. Compound 24 also inhibited IL-17 production from the lung BAL cells (IC50 = 350 nM) and PBMCs (IC50 = 147 nM) of chronic obstructive pulmonary disease (COPD) patients. A spirocyclic modification of the central core (e.g., 25, RORγt Ki = 16.6 nM in the binding assay) was recently disclosed by Lilly.59 Compound 25 (Figure 6) displayed more than 700-fold selectivity against RORα and RORβ isoforms. In a HEK293 RORc LBD-GAL4 assay and hPBMC-IL-17 assay, it was shown to have IC50 values of 21.8 nM and 20 nM, respectively. In glucose-6-phosphate isomeraseinduced arthritis model in mice, compound 25 displayed 75% reduction in the clinical score at an unusually high dose of 1000 mg/kg po.59 Researchers at AstraZeneca reported isoindoline derivatives exemplified by 26 (Figure 6).60 The key feature of this compound is the conformational restriction applied at the methylene group of linker amide with the neighboring phenyl ring constructing an isoindoline core. Recently, discovery efforts for the identification of their clinical candidate AZD-0284 (26) were



described.61 The early SAR involve structural optimization of compound 17 eying improved cellular potency and better physiochemical properties. Reduced lipophilicity and improved solubility were achieved by employing hexafluoroisopropanol moiety as an optimized group in the left portion of 17 (Figure 6). Further improvement in potency and physiochemical properties was achieved by introducing polar groups at the methylene group of the central linker. These groups allow more polar interactions in the LBD of RORγ. Compound 26 was finally shortlisted as their clinical candidate, the profile of which was compared with 22 (VTP-43742, Figure 6). It inhibited RORc in FRET assay with an IC50 value of 40 nM. The cell potency measured in human Th17 cells was better when compared with 22 (IC50 = 16 nM (26) vs. 40 nM (22)). Compound 26 showed an improve solubility (380 µM (26) vs. 17 µM (22)) and appreciable free fraction in human plasma (16% (26) vs. 0.5% (22)). The oral bioavailability in rats was moderate (F(%): 34 (26), 72 (22)), however, it has shown excellent bioavailability in the dog (F(%) = 96). Compound 26 was reported to inhibit IL-17 production in all CCR6+ subsets and reduced skin inflammation in vivo. Cocrystal structure of 26 bound to the RORγ-LBD revealed an additional hydrogen bond interaction through an oxygen atom of the N-acetyl group. Other three hydrogen bond interactions are similar as expected for this class of compounds (e.g., 16, 22, Figure 6). The hexafluoroisopropanol moiety interacts with helices 11/12 via water-mediated hydrogen bonds. (Crystal structure not deposited in PDB). A team from Boehringer recently described a series of pteridine derivatives as RORγ inhibitors (e.g., 27, Figure 6) with the unique non-amide linker different from the compounds discussed above.62 However, compounds have free NH group, which may still involve in the hydrogen-bonding with Phe377. Compound 27 (RORγ IC50 = 60 nM in reporter gene assay) was shown as a potent inhibitor with favorable metabolic stability in HLM.62


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(4)

Amide/Bis-amide derivatives The RORc inhibitors discussed in this section have the presence of one or two amide groups

each involved in key hydrogen bond interactions either directly or water-mediated with Glu379, His479, and Phe377 and imparts them a very good potency (Figure 7). Researchers at Biogen reported one of the first of its kind. Structure-based approach with an intention to incorporate polar groups into the molecule to allow more hydrogen-bonding interactions led to the identification of biarylamide derivative 28 (Figure 7).63 The IC50 value in RORc FRET assay and EC50 value in the RORc GAL4 cellular assay were found to be 29 nM and 97 nM, respectively. The cocrystal structure of compound 28 with RORγ protein (PDB: 4ZJR) revealed a prominent hydrogen bond through carbonyl of head amide group with the backbone residue Glu379 at the pocket entrance. The OCH2CF3 group occupies a nearby small pocket and twisted the internal amide group for the second hydrogen bond interaction with His479 on H11. This second hydrogen bond interaction disrupts the agonist lock between His479 (on H11) and Tyr502 (on H12), resulting in inverse agonistic activity. The incorporation of N-CD3 group improved PK properties in rats, especially reduced clearance was observed over corresponding N-CH3 derivative by lowering N-demethylation metabolism (F(%) = 41, T1/2 = 9.6 h). Reduction in lipophilicity to improve solubility was achieved by synthesizing pyrazole analog 29 (Figure 7).64 In addition to improved solubility, compound 29 has shown excellent potency in RORγ FRET (IC50 = 3 nM) and RORγ GAL4 (EC50 = 8.1 nM) assays and suppress IL-17 production in splenocytes (EC50 = 38 nM). The cocrystal structure of 29 (PDB: 4ZOM) with RORc-LBD showed similar binding interactions as observed for 28. A team from GSK disclosed a series of diamide derivatives (e.g., 30, Figure 7) containing piperazine carboxamide functionality.65 The SAR involved exploration of a variety of



substituents at both the amide terminus. The cyclopentyl group was one of the highly explored substituents at the piperazine amide terminus, while the majority of substituents explored at the aryl amide terminus have hydrogen bond acceptor functionality. Compound 30 was shown to have RORγ inhibitory activity in both dual FRET (IC50 = 97 nM) and Th17 cell differentiation (IC50 = 31 nM) assays. In a mouse EAE model of MS, compound 30 delay onset of EAE and also lowered clinical score at doses of 3, 10 or 30 mg/kg bid, po.65 In a recent publication by Novartis, compound 31 (RORc IC50 = 1.2 nM in the TR-FRET assay) was tested in rats to show reduced delayed-type hypersensitivity ear swelling response at 3 mg/kg bid, po.66 However, oral administration of 31 at 10 mg/kg bid for 13 weeks showed thymic aberrations including early lymphocytolysis. The above result suggests a possible risk of T cell lymphoma with RORc inhibitors upon chronic therapy. A series of structurally similar piperazine derivatives with the imidazopyridine core (e.g., 32, Figure 7) was further disclosed by Novartis.67 In a RIP140 coactivator peptide displacement assay and IL-17 production assay in human whole blood, 32 displayed IC50 values of 13 nM and 168 nM, respectively. Compound 32 showed moderate oral bioavailability in rats (F(%) = 23) and showed appreciable free fraction in the rat (25.6%) and human (31.2%) blood. The X-ray structure of compound 32 with RORγt [264-491] construct (PDB: 5M96) revealed that the two nitrogen atoms of the pyrimidine ring formed water-mediated hydrogen bonds to residues Arg367, Leu287, and Glu379. The adjacent amide NH group in 32 makes a hydrogen bond with the carbonyl of the backbone of Phe377 similar to that observed for arylsulfonyl class of compounds through the NH of linker amide (e.g., 16, Figure 6). The imidazopyridine core occupies a pocket formed by Met365, Val376, Leu400, Phe401, and Ser404. The carbonyl group from the second amide group present at the piperazine core provides a hydrogen bond contact


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with His479 similar to that observed for 28 through internal amide group. The terminal cyclopentyl group will clash with Trp317 if helix 12 is in the agonist position.17 A structurally related sulfonamide modification (33) (Figure 7) was disclosed by Daiichi Sankyo.68 In the binding assay with RORγt-LBD, 33 displayed an IC50 value of 89 nM and found to be selective against RORα, RORβ, and PPARγ in luciferase reporter assay. In an IL-23induced mouse model of psoriasis, significant reductions in epidermal thickness and IL-17A levels were observed for 33 when dosed orally at 100 mg/kg. A second confirmation of efficacy was achieved in K5.Stat3C transgenic mouse, which resembles human psoriasis. Oral administration of 33 attenuated 12-O-tetradecanoylphorbol-13-acetate-induced psoriasis-like lesions by improving scaly and erythematous change with attenuation of ear thickness.68 Pfizer disclosed a series of azaindole derivatives exemplified by compound 34 and 35 (Figure 7).69 The striking feature of this molecule is the presence of rigid azaindole core unlike flexible methylene linker present in molecules 30-32. The other noticeable change is the presence of piperidine heterocycle instead of piperazine. Compounds of this invention are always substituted with CF3 (34), OCH3 (35), and CH3 (not shown) groups at the para-position of the pyridine from the azaindole core. RORγ inhibitory activity was confirmed in both TR-FRET assay (IC50 = 4.7 nM (34), 11.8 nM (35)) and in the IL-17 production assay (IC50 = 9.4 nM (34), 29.8 nM (35)). A recent publication by Takeda described the trimethylsilyl analogs (36, Figure 7)70 with conformationally restricted bis-amide linker modification to their previously disclosed aliphatic linker derived bis-amides.71 The selection of an unusual trimethylsilyl group was based on the finding that the silyl compounds have shown improved functional activity when compared with there tert-butyl counterparts (not shown).72 The increase lipophilicity of the trimethylsilyl group



over tert-butyl could be the reason for this phenomenon. A similar observation was earlier reported by Hashimoto’s group where they have shown increased ROR inhibitory activity for silylated compounds.73 Compound 36 with tetrahydroisoquinoline core inhibited RORγt with IC50 values of 3 nM and 23 nM in the binding assay and a cell-based reporter gene assay, respectively. The X-ray cocrystal structure of a closely related analog with RORγt-LBD revealed that the trimethylsilylphenyl group was extended toward the hydrophobic pocket (PDB: 6B30).72 Amide groups, one, with NH group and other with the carbonyl group formed hydrogen bonds with the backbones of Phe377 and Glu379 (Figure 7).72 Compound 36 was shown to have excellent oral bioavailability in mice (F(%) = 94). Furthermore, 36 had shown excellent in vivo efficacy with an ED50 value of 2.8 mg/kg po in reducing IL-17A gene expression in IL-23 treated mice.70 Takeda recently described the discovery efforts and pharmacological profile of their clinical candidate 37 (TAK-828F, free form of TAK-828, Figure 7).74,75 The SAR was directed to reduce lipophilicity of compound 36 (clogP = 5.8) with three significant changes: First, to replace trimethylsilyl group with dimethylindanyl group, second, core modification with tetrahydronaphthyridine and third, replacement of the flexible carboxylic acid linker with a rigid structure. The optimized compound 37 (clogP = 3.9) was identified with improved RORγt IC50 values of 1.9 nM, 6.1 nM, and 102 nM in a binding assay, cell-based reporter gene assay, and human PBMCs, respectively.75 It was found to be highly selective against related ROR isoforms and a panel of 20 NRs.74 In Th17 and Th1 cells differentiation assay from human CD4+ T cells, it selectively suppressed Th17 polarization (IC50 = 28 nM) and also decreased Tc17 cells differentiation from human CD8+T cells (IC50 = 9.5 nM).75 In human whole blood assay, it inhibited IL-17, IL-17F, and IL-22 production with IC50 values of 120, 430, and 1600 nM,


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respectively.75 Compound 37 suppressed the Th17 cells differentiation and simultaneously increase the expression of Treg transcriptional factor Foxp3 in CD4+ T cells in Th17-skewing condition improving Th17/Treg cells imbalance.75 Owing to the good PK in mice (F(%) = 96, T1/2 = > 4 h), it was further evaluated in EAE model where it displayed 50% reduction of the clinical score upon oral dosing at 1 mg/kg bid in mice.74 Furthermore, 37 was also shown to have in vivo efficacy in the activated T cell transfer colitis model and IL-23-induced mouse psoriasis model upon oral dosing.74 The cocrystal structure of 37 with RORγt (PDB: 6BR3) revealed similar interactions as described for 36 with an additional water-mediated hydrogen bond interaction observed for nitrogen atom of the pyridine ring with Gln286.74 The methoxy group was involved in a water-mediated interaction with Arg364. However, Takeda recently announced the discontinuation of 37 based on the critical toxicological findings in both monkey and rats.76 The HTS campaign at Japan Tobacco followed by ligand efficiency (LE), and a fraction of saturated carbons (Fsp3) guided SAR led to the identification of compound 38 (human GAL4 EC50 = 34 nM, LE = 0.29, Fsp3 = 0.64) as an orally active RORγ inhibitor (Figure 7).77 The Xray structure of an analog (PDB: 5AYG) revealed the U-shape binding in the LBP of human RORγ. The NH from linker amide group made a direct hydrogen bond with the backbone carbonyl of Phe377, while the water-mediated hydrogen bond was observed to Arg364 through carbonyl. A second water-mediated hydrogen bond was observed to Glu379 through a nitrogen atom from the triazole ring serving a role of the carbonyl from a second amide group. Furthermore, the compound 38 (F(%) = 78 in mouse), when administered at 30 mg/kg po to mice treated with MOG/PTX and a CD3 antibody suppressed IL-17 production by 45% after 8 h. (5)

Allosteric inhibitors



The RORc inhibitors discussed so far were shown to occupy orthosteric-binding pocket in RORc. Researchers at Merck identified a novel allosteric binding site adjacent to it with a series of allosteric ligands 39-42 (Figure 8).78 The cocrystal of RORγt-LBD and 39 (PDB: 4YPQ) revealed a new binding site different from the canonical orthosteric NR ligand-binding site and is formed by helices 4, 5, 11, and the reoriented flexible H12 (Figure 9). The ortho-substituted trifluoromethyl and chloro moieties impart a specific rotation to the phenyl group of 39 and address hydrophobic sites near helix-11 and helix-3 in the allosteric pocket (Figure 9). The carboxylic acid group of 39 involved in hydrogen-bonding interactions with the backbone NH of Aln497 and Phe498 and also with the side chain of Gln329, suggesting the importance of the carboxylic group in this class of compounds. The unique conformation induced by the binding of 39 prevents interaction with coactivator peptides, which usually bind RORγt at the AF-2 domain. The potency of compounds has been evaluated in the biochemical assay (RORγt FRET IC50 = 6.1 nM (39), 3.8 nM (40), 1.9 nM (41), 2 nM (42)) and functional assay of IL-17 production (hPBMC IC50 = 39.6 nM (39), 9.4 nM (40), 13 nM (41)).78 The additional fluoro groups and polar functionalities in 40 and 41 showed a positive impact in improving potency. Compounds 40 and 42 were found to be > 100-fold selective when tested against ROR isoforms and panel of NRs. At 1 µM concentration, compounds 39 and 42 were shown to suppress IL-17A secretion by 70% in cells derived from patients with AS. Furthermore, they were shown to reduce the number of IL-17A+ cells within the CD4+ T-cell compartment by 50% in cluster of autoimmune inflammatory diseases, including AS, psoriatic arthritis, RA, and IBD.79 A recent patent from Merck described a cyclopropyl modification of compound 42 (i.e., 43, Figure 8) in order to improve PK profile.80 Compound 43 (RORγt FRET IC50 = 2.5 nM) was shown to have low plasma clearance (5 ml/min/kg) in comparison with 42 (76 ml/min/kg) in rat.80


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To address the potential metabolic liability of the 1-acyl-indazole moiety, researchers at Genentech came up with the imidazo[1,5-a]pyridine (e.g., 44, Figure 8) central core that has benzoyl group attached to a carbon atom.81 Compound 44 (RORc SRC1 EC50 = 2 nM) suppressed IL-17 production in hPBMCs with an IC50 value of 17 nM and displayed 250-fold selectivity against ROR isoforms. The structural modification also facilitated compound 44 and related analogs to improve their selectivity over PPARγ in comparison with compound 39. However, in a rat PK experiment, 44 demonstrated a high plasma clearance (CLp = 130 mL/min/kg) exceeding rodent liver blood flow (55 mL/min/kg), indicating that extrahepatic clearance mechanisms may also be participating in the metabolism of 44. Galderma disclosed a series of phenoxyindazoles (e.g., 45, Figure 8) in line with their interest in developing RORγ inhibitor suitable for topical application.82 In a recombinant RORγt/GAL4 cellular assay, 45 displayed an IC50 value of 31 nM and inhibited IL-17 production in human CD4 cells with an IC50 value of 40 nM. The presence of N,N-dimethylamide group was crucial for its selectivity against retinoic acid receptor gamma (RARγ). Although high intrinsic clearance in human hepatocytes was suitable for its use as a topical agent, phototoxicity in cellular assay prevented its further evaluation. The X-ray structure of 45 bound to RORγ (PDB: 5LWP) offered a further confirmation for the compound to be an allosteric ligand. (6)

Miscellaneous inhibitors The isooxazole derivative 46 (TMP778, IC50 = 5 nM (FRET) and 17 nM (GAL4) assays,

Figure 10) was earlier reported to have anti-psoriatic activity in mice.83 It was shown to reduce ear thickness, epidermal hyperplasia, and inflammatory cell influx in the IMQ-induced mouse model of psoriasis at 20 mg/kg bid, s.c., by a team from Tempero.83



A team from Innovimmune published several patent applications on a common pyrazole motif (e.g., 47-49, Figure 10).84-86 In a separate disclosure, a series of compounds with pyrazole moiety linked to indole (e.g., 47),84 azaindole (e.g., 48),85 and pyrazole (e.g., 49)86 central cores were described. Selected compounds of the invention were evaluated for their ability to inhibit cytokine production in human PBMCs. All exemplified compounds have inhibited IL-17A, IL17F, IL-21, and IL-22 production with an IC50 value of < 10 µM. Recently, a preclinical profile of their RORγ inhibitor (INV-17) was disclosed.87 The compound was assessed for its therapeutic efficacy in IMQ-induced mouse model of psoriasis. INV-17 was dosed orally at 15 mg/kg od in BALB/c mice for 5 days. A significant reduction of ear thickness was observed which was more pronounced than Tofacitinib citrate, a janus kinase inhibitor (JAK 1 and 3) used as a comparator at 30 mg/kg bid, po. Nuevolution and Almirall have collaborated for discovering RORγt inverse agonists.88 While Nuevolution would evaluate RORγt inverse agonists for IBD indication, Almirall would develop them for dermatological indications including psoriatic arthritis.88 Pyrimidine derivatives exemplified by 50 were earlier disclosed by Nuevolution as RORγ inverse agonists (Figure 10).89 Several examples from the Nuevolution patent contained polar groups such as acid, alcohol, amide, and sulfonyl at one end while the other end of the molecule usually has phenyl ring substituted with lipophilic substituents such as trifluoromethyl and alkyl. Compound 50 inhibited RORγ activity in the Gal4 assay by more than 80% at 1 µM. Furthermore, it was assessed in both EAE and CIA mouse model of autoimmune diseases where oral administration of 50 at 10 mg/kg and 30 mg/kg bid doses displayed a disease attenuating effect. A team from Esalier Bioscience disclosed a series of biaryl derivatives (e.g., 51 and 52, Figure 10) as soft drugs for the topical treatment of psoriasis.90 Structurally they are similar to 2


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(SR2211) disclosed earlier by Scripps Florida.33 The ester derivative 51 was shown as a potent inhibitor of RORγt in the Gal4 assay (IC50 < 1 µM). The corresponding carboxylic acid derivative 52, which may have been observed in systemic circulation upon enzymatic hydrolysis of ester, was inactive with an IC50 value of > 10 µM. The design of such inhibitors may provide a safe delivery of a topical RORγt inhibitor with a minimal systemic toxicity. A team from Arrien disclosed structurally distinct indanone derivatives exemplified by 53 as RORγt antagonists (Figure 10).91 The preferred compounds in this publication have methoxy group on the phenyl ring of the central core and benzyl group on 5-membered cyclopentanone ring. Trifluoromethyl group was extensively used as a substituent on the benzyl group. The representative compound 53 displayed IC50 values less than 500 nM in FRET assay, RORγtactivated IL-17A assay in HEK 293 cell lines, and a CD4+ T cell IL-17 production assay. The preclinical profile of their clinical candidate ARN-6039 (structure not disclosed) was recently described.92 The activity of ARN-6039 was demonstrated in a RORγt-activated IL-17A Prom/LUCPorter assay in HEK 293 cells (IC50 = 360 nM) and in IL-17 production from CD4+ T cell assay (IC50 = 220 nM).92 It was found to be selective against related isoforms, and has moderate oral bioavailability (F(%) = 37) and has no hERG liability. The up-take data indicated that ARN-6039 might act in the CNS as well as the blood to inhibit inflammation and demyelination. Oral administration of ARN-6039 (10 mg/kg) before anti-CD3e antibody administration in mice resulted in a 50% reduction of IL-17 production. In a mouse model of EAE, once a day dosing of ARN-6039 for 28 days protected mice from EAE development at 40 mg/kg dose. ARN-6039 showed no signs of toxicities up to doses of 2000 mg/kg from their toxicity studies.



A structurally distinct series of indole derivative exemplified by 54 (IC50 < 100 nM in RORγ GAL4 assay) was disclosed by AbbVie (Figure 10).93 The key SAR in patent examples was directed to the variations at amide portion of the molecule. The piperazine ring shown in 54 was frequently replaced with morpholine and piperidine. A large number of examples have piperidine ring substituted with the carboxylic acid group. AbbVie was successful in identifying its clinical candidate (ABBV-553), however, clinical development was later ceased.22 Pyridazine derivatives exemplified by 55 and 56 were disclosed by Genentech as modulators of RORc (Figure 10).94 Majority of examples have 2,6-difluorophenyl ring substituted at 3rd position of the pyridazine ring. The chemotype optimization was mainly focused on the pyrimidine ring attached with a central core and was substituted with a variety of groups. In the binding assay, compound 55 with an unsubstituted pyrimidine ring displayed an IC50 value of 15.8 nM, while 56 with the piperidinyl substituent showed improved binding with an IC50 value of 2 nM. Researchers at Phenex previously described a series of pyrrole derivatives (e.g., 57, Figure 11) as RORγ modulators.95 The subsequent replacement of the pyrrole ring with oxazole,96 thiazole,96 and pyrazole97 rings was reported in separate publications. Recently, biological evaluation of thiazole-based inverse agonists of RORγt (e.g., 58, 59, Figure 11) derived from 57 was published by a team from Phenex and Janssen.98 During SAR, compounds were initially evaluated in a ThermoFluor binding assay using RORγ. Selected compounds were then tested in the RORc LBD-GAL4 assay in HEK293T cells and analyzed for their ability to inhibit IL-17 production in human whole blood. Compounds were further evaluated for their liability of PXR and RORβ inhibition associated with this chemotype. The initial SAR led to the identification of compound 58 (RORc IC50 = 1.2 nM) with a moderate EC50 value of 505 nM in human whole


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blood assay (efficacy compared to 62, JNJ-54271074, Figure 11). Compound 58 has shown limited potential for PXR inhibition, however, it was found to inhibit RORβ (IC50 = 83 nM) in the similar assay as described for RORc. Additional optimization resulted in the identification of compound 59 (RORc IC50 = 1.6 nM) with high selectivity over PXR and RORβ. The EC50 value in human whole blood was found to be 98 nM. The X-ray structure of 58 bound to LBD of RORγt was prepared to understand the binding mode of this series of compounds (PDB: 6CVH). Compound 58 almost entirely occupied LBD, while the carboxylic group was shown to project out of the LBP and was partially solvent-exposed. These results explain the broad tolerance of the polar groups at C-2 amide region of thiazole ring. The amide and terminal alkyl-CF3 moieties projects toward the AF-2 region of LBD and approached helix 10/11. Despite extensive SAR efforts, the entire drug like parameters could not be achieved in this series and further SAR evaluation is warranted. Additional work based on the thiazole chemotype was published by Janssen in a recent patent disclosing a series of 6-aminopyridin-3-yl thiazole derivatives exemplified by 60 (Figure 11).99 The amino group at 6th position on pyridine ring was found to be crucial for the biological activity, while CF3 group was desirable for high potency. Compound 60 in RORγt ThermoFluor binding assay displayed Kd value of 0.17 nM, and in a human Th17 cell assay, it showed the IC50 value of 2.8 nM. Quinolinyl derivatives as RORγt inhibitors were extensively evaluated by Janssen.100-103 The SAR of quinoline tertiary alcohol modulators of RORγt (e.g., 61 and 62, Figure 11) was recently described by the team from Janssen.104 The HTS using ThermoFluor assay followed by thorough optimization of 2-, 3-, and 4-positions on the quinoline core led to the identification of compound 61 (IC50 = 170 nM in cell-based reporter assay). The cocrystal structure of 61 bound



to LBD of RORγt revealed that the 4-chloro-2-methoxyquinoline core positioned itself between the side chains of Met365 and Phe378, forming an edge-to-face π-π interaction with the latter (PDB: 5W4V).104 The trifluoromethyl pyridine ring is sandwiched between three aromatic side chains, making face-to-face contact with His323 and edge-to-face interactions with Phe377 and Phe378. The pyridine nitrogen accepts a hydrogen bond from the backbone amide of Glu379. The nitrogen from N-methylimidazole core was shown to make a water-mediated hydrogen bond with the Arg367. The anti-arthritic activity of compound 62 (JNJ-54271074) was reported in a separate publication.10 It was shown to have IC50s of 8 nM in a RORγt FRET assay, 9 nM in a one-hybrid reporter assay, and 30 nM in a two-hybrid corepressor peptide NCoR assay.10 A dose-dependent reduction in the arthritic score was demonstrated in a mouse model of CIA with 32%, 46%, and 78% reductions observed at 10, 30, and 60 mg/kg bid, po doses, respectively. It inhibited IL-17A production in PBMCs from RA subjects with an IC50 value of 5 nM. In an IL23-induced mouse model of dermatitis, oral administration of 62 showed significant reduction of total skin histology score, skin abscesses, and acanthosis at 30 and 60 mg/kg bid doses.10 Janssen in collaboration with Phenex is developing JNJ-3534 (structure not disclosed) for psoriasis indication. Currently, the molecule is undergoing Phase I clinical evaluation.23 In a recent press release, Reata Pharmaceuticals announced the initiation of Phase I trial of their oral inhibitor of RORγt (RTA-1701, structure not disclosed).27 Preclinical profile of RTA1701 was recently described.105 It was shown as isoform-selective, potent inhibitor of RORγt and inhibits IL-17 production in human PBMCs. Furthermore, RTA-1701 was reported to have efficacy in animal models of autoimmune disease, including the CIA mouse model of RA and the EAE mouse model of MS. In a separate report, PK of RTA-1701 and its effects on ex vivo stimulation of IL-17A production in the whole blood after oral administration to cynomolgus


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monkeys were described.106 Monkeys received a single administration of RTA-1701 (0.3, 3, 30, or 300 mg/kg) and after a one-week washout, the same doses of RTA-1701 were given once daily for 14 consecutive days. RTA-1701 exhibited oral bioavailability in monkeys and produces significant and dose-dependent suppression of ex vivo stimulation of IL-17A secretion in whole blood at 24 and 30 hours after single and repeat dosing. IL-17A levels normalized within 72 hours after a single dose. Reata disclosed their RORγt inhibitors in two separate patent publications. The first disclosure was C-4 modified oleanolic acid derivatives (e.g., 63, Figure 11) reported as inhibitors of IL-17.107 Compounds in this series are close analogs of Bardoxolone methyl, an NRF2 (nuclear factor erythroid-derived 2-related factor 2) activator, evaluated in a phase III trial for the treatment of chronic kidney disease.108 The C-4 position in this series was modified with groups such as substituted alkyl, cycloalkyl, heterocyclyl, hydroxy, and amino. In RORγ GAL4 cellular assay, 63 displayed an IC50 value of 115 nM and inhibited IL-17 production from human CD4+ T cells with an IC50 value of 18 nM. In AREc32 luciferase reporter assay, which allows assessment of the endogenous activity of NRF2 transcriptional factor in cultured cells, 63 doubles the NRF2ARE (antioxidant response element) luciferase activity at 56 nM concentration. In a very recent patent, Reata disclosed pyrimidine-based tricyclic enone derivatives exemplified by 64-69 as inhibitors of RORγ.109 The compounds of the invention were evaluated for their biological activity using similar assays as described above. The major structural modifications were reported on the pyrimidine ring. The group at R1 was 2-fluorophenyl in the majority of examples (Figure 11). The other R1 substituents such as cycloalkyloxy and 5-membered heteroaryls have displayed appreciable activity in few examples. The 6- to 10-membered N-containing heteroaryl rings especially pyridine and quinoline as R2 substituents (Figure 11) have shown relatively



better activity compare to its phenyl counterpart (not shown). The other R2 modifications such as substituted alkyl and saturated heterocycles were not tolerated (Figure 11). The compound 64 with phenyl as R1 substituent and 3-methyl-4-pyridyl as R2 substituent displayed excellent potency (RORγ IC50 = 40 nM, hIL-17 IC50 = 39 nM, Figure 11). Compound 65 with 2fluorophenyl as R1 and 4-quinolyl as R2 showed similar potency (RORγ IC50 = 52 nM, hIL-17 IC50 = 32 nM) as that of 64 (Figure 11). The C-4 position in the enone-containing ring was also modified. Changing methyl to n-propyl group in 65 gave compound 66 with improved potency (66, RORγ IC50 = 36 nM, hIL-17 IC50 = 16 nM). Compound 67 with gem-dimethyl modification of 65 displayed slightly lower RORγ inhibitory activity, but comparable IL-17 potency (67, RORγ IC50 = 71 nM, hIL-17 IC50 = 28 nM). The presence of cyano and the alkene group was prerequisite for the potency as changing it to amide and saturating double bond, respectively, furnished compounds with the diminished potency (not shown). The central ring contraction from cyclohexyl (i.e., 65) to cyclopentyl (i.e., 68) was found to be detrimental for the potency (68, RORγ IC50 = 245 nM, hIL-17 IC50 = 147 nM). However, ring expansion from cyclohexyl (i.e., 64) to cycloheptyl (i.e., 69) was done with the retention of activity (69, RORγ IC50 = 37 nM, hIL-17 IC50 = 44 nM). The R stereochemistry of the C-H at the fusion of the enonecontaining ring and the central ring is favored for the enhancement of potency (Figure 11). Compounds have also been tested for their potential to activate NRF2 and found to double NRF2-ARE at 5-10 fold higher concentration than their RORγ IC50 values. For e.g., compound 64 (RORγ IC50 = 40 nM) doubles NRF2-ARE at ~7 fold higher concentration (278 nM). Importantly, compound 69 (RORγ IC50 = 37 nM) with cycloheptane central ring doubles it at a much higher concentration (892 nM, ~24 fold). Reata has claimed their clinical candidate to be an allosteric ligand. Structurally this class of inhibitors is quite different from the earlier


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allosteric inhibitors. Hence, cocrystal data are required to substantiate their classification into an allosteric class of inhibitors. CLINICAL UPDATE Vitae/Allergan disclosed the clinical data of the most advanced molecule (22, VTP-43742/AGN 242428, Phase II). Compound 22 was evaluated in two, randomized, double-blind, placebocontrolled studies in healthy volunteers.110 Compound 22 in both single ascending dose (SAD) study (7 dose levels, 30-2000 mg) and multiple ascending dose (MAD) study (5 dose levels, 1001400 mg, od, 10 days) was safe and well tolerated at all dose levels. In the SAD study, it had a terminal half-life of ~30 h suitable for once a day dosing. In an ex vivo whole blood assay of IL17A secretion, 22 suppressed IL-17A secretion in a dose-dependent manner with > 90% inhibition observed at the higher doses. Compound 22 was then evaluated in a randomized, double-blind placebo-controlled Phase IIa trial in psoriasis patients over a four-week period. A significant reduction in the Psoriasis Area Severity Index (PASI) score relative to the placebo was observed in the 350 mg (24%) and 700 mg (30%) dose groups.111 The rate of reduction in PASI score showed an increasing trend between weeks three and four, suggesting the potential for greater reductions in PASI scores with the longer duration of treatment. No serious adverse events were reported in this study, however, in the 700-mg dose group, reversible transaminase elevations were observed in four patients. In a recent press release, the discontinuation of 22 was reported because of unknown safety concerns.112 Compound 14 (GSK-2981278, Figure 4) was evaluated in the clinic for the topical treatment of psoriasis by GSK. The clinical outcome of phase I randomized controlled trial to evaluate the safety and clinical effect of topically applied ointment of 14 in a psoriasis plaque test was recently disclosed.113 Subjects (n = 15) were treated with 200 µL of 14 ointment (0.03%, 0.1%,



0.8% or 4%), vehicle, and betamethasone valerate 0.1% cream (positive control) once daily over 19 days. However, clinical assessment results showed no improvement in psoriatic lesions following treatment with 14 or vehicle ointment. The lack of efficacy is attributed to the insufficient drug exposure at the target site, small treatment area, and the need for systemic inhibition of RORγ. GSK recently announced that it may terminate, partner or divest 14.114 Development of clinical molecules TAK-828 (37), ABBV-553 and JTE-151 was ceased, while the outcome of other clinical molecules, including ARN-6039 (Phase I), JNJ-3534 (Phase I), AZD-0284 (26, Phase I), and JTE-451 (Phase I) has not been so far. RTA-1701 is an allosteric inhibitor of RORγt for which initiation of Phase I trial has been recently reported.27 PERSPECTIVE The discovery of RORc inhibitors for the treatment of autoimmune disorders has received much attention in the past five years. With several molecules currently in the clinical and preclinical evaluation, this area of research continues to evolve. The broad consensus among highly diverse RORc inhibitors is the presence of lipophilic motif on one end attached to a polar moiety (most often hydrogen bond acceptor) on the other end via a variety of linkers or central cores. Availability of crystal structures with ligands offers significant insight on how to modulate RORc inverse agonistic activity. In general, ligands that stabilize helix 12 of protein are agonists, while those, which destabilize are inverse agonists. Even minor variation in the structure is found to reverse the biological nature of the ligand. For example, compound 12 with benzene sulfonamide moiety displayed agonist nature, while compounds 10 and 11 with benzyl sulfonamide moiety were inverse agonist (Figures 4 and 5). Current inhibitors of RORc have shown high selectivity over related NRs. As many of them are derived from the HTS campaign, SAR was directed to achieve selectivity against their primary biological target in parallel to


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improve RORc inverse agonist activity. Compounds 2-4 and 5 illustrate the SAR studies in which the selectivity was achieved against LXR and PXR, respectively (Figures 2 and 3). Compound 43 illustrates the SAR exploration in which C-acylated imidazo[1,5-a]pyridine derivatives have shown improved PPARγ selectivity when compared with N-acylated indazole derivative (39) (Figure 8). Isoform selectivity in RORc inhibitors initially remained an issue, but that has been mostly resolved, as current inhibitors possess excellent isoform selectivity. As described in Figure 1, compounds 2 and 3 have hexafluoroisopropanol-substituted phenyl ring similar to 1 but differ in having a biaryl core in place of sulfonamide group and an additional piperazine moiety bearing hydrogen bond acceptor groups at the terminal position. The above structural changes offered compounds 2 and 3 an improved selectivity for RORc, unlike 1, which is a non-selective RORα/c inverse agonist. Compound 17 (Figure 6), one of the earliest compounds in aryl sulfonyl class of RORc inhibitors was described as a dual inhibitor of RORβ/c.50 However, few inhibitors from the same class having variations at the lipophilic portion and having similar hydrogen bond acceptor aryl sulfonyl moiety are reported to be selective RORc inverse agonists (e.g., 2256 and 25,59 Figure 6). This has led to the inference that modulating a lipophilic portion of the molecule may improve RORβ selectivity. The solubility is another critical issue with these significant lipophilic RORc inhibitors. Discovery of 26 (AZD-0284, Figure 6) was dominated by the structural modifications that improve solubility by reducing LogD.61 To achieve this as discussed, polar groups were introduced at the linker which has served to improve both potency and solubility.61 The identification of selective RORγ inhibitor against related isoforms addressed the toxicities associated with RORα inhibition (ataxia) and RORβ inhibition (motor defects). RORγ



and its isoform RORγt have identical LBDs. This makes selective inhibition of RORγt, which is present only in the thymus, a challenging goal to achieve. The undesired inhibition of RORγ in non-immune cells poses a concern for potential side effects. Besides its beneficial effect in regulating IL-17-mediated diseases, its excessive inhibition may have several theoretical concerns. Recent studies with RORγt inverse agonist (42, MRL-248, Figure 8) revealed that the pharmacological inhibition of RORγt decreases double-positive CD4+CD8+ thymocyte life span, skews TCRα gene rearrangement and limits T cell repertoire diversity.115 The chronic study in rats with RORc inhibitor showed thymic aberrations suggesting a possible risk of T cell lymphoma with RORc inhibitors upon chronic therapy.66 Furthermore, a conditional RORγ/γt knockout mouse (RORc CKO) where the RORc locus can be deleted in adult animals was designed to understand whether lymphomas observed in the RORc KO mice116 would develop in an animal with an intact, fully developed immune system.117 The study confirmed findings that RORc CKO animals also develop lymphoma in a similar time frame as embryonic RORc knockouts. Interestingly, in animals where the gene deletion is incomplete, the thymus undergoes a rapid selection process which replaces RORc-deficient cells with remnant thymocytes carrying a functional RORc locus. Subsequently, these animals did not develop lymphoblastic lymphoma. These observations have raised a notion that RORc partial inverse agonists (e.g., 8, Figure 3) may have a better safety profile than full inverse agonists. However, the balance between safety and the desired therapeutic efficacy with the partial inverse agonists needs to be demonstrated. RORγ loss of function mutations have been identified in humans.118 Seven patients from three ethnic groups were shown to lack functional RORγ and RORγt.118 Importantly, only a mild Tcell lymphopenia was observed, and these patients were free from any lymphomas. However, they have shown increased susceptibility to candidiasis and mycobacteriosis.118 Long-term


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toxicological evaluation of RORc inhibitors is therefore needed to preclude any toxicity that may arise in humans upon chronic use. Despite potential concerns of RORc inhibition, it is still a viable approach for some, if not all, of the autoimmune diseases. The preclinical data of current RORc inhibitors endorse their use for the treatment of psoriasis and MS. Although a few molecules have shown efficacy in a mouse CIA model, clinical usage of these inhibitors for RA is still a forward-looking goal. However, there may be a more immediate application in combination therapy for RA. So far, the majority of molecules advanced into the clinical trials found psoriasis as their primary indication through topical as well as systemic administration. The initial data of the most advanced molecule 22 (VTP-43742, Figure 6) in psoriatic patients upon oral dosing were encouraging, however, safety concerns prevented further development of this molecule. Furthermore, the lack of efficacy of topically applied 14 (GSK-2981278) in a psoriasis plaque suggests that systemic inhibition of RORc would be more desirable.113 As discussed previously, IL-17 antibodies exacerbate Crohn’s disease, which may be due to undesired inhibition of RORγt in innate lymphoid cells (ILC). However, a recent investigation with RORγt inverse agonist (18, GSK805, Figure 6) in mice infected with Citrobacter rodentium demonstrated that transient inhibition of RORγt provides therapeutic benefit in mouse models of intestinal inflammation by selective targeting of Th17 cells, but not ILCs.119 TAK-828 (37, its free base) was advanced into the clinic with the intended use for the treatment of Crohn’s disease. Unfortunately, before valuable insight was derived, the trial was discontinued based on the critical toxicological findings in both monkey and rats, combined with its potential for teratogenicity in humans.76 The discontinuation of VTP-43742 and TAK-828 due to safety concerns reaffirm the importance of a critical evaluation of preclinical toxicity in animals. The LBP of RORc is mainly hydrophobic and



allows binding of inhibitors with substantially high lipophilicity. Consequently, these inhibitors have shown excellent efficacy in a preclinical model of MS, possibly as a result of their appreciable CNS penetrability.51 Based on these findings, Arrien has advanced its candidate ARN-6039 in Phase I trial for MS indication. Another application of RORc inhibitors is in respiratory indications. As discussed earlier, RORc inhibitor 24 (Figure 6) was shown to inhibit pulmonary inflammation and emphysema induced by cigarette smoke in male C57/BL6 mice. Moreover, 24 also inhibits the IL-17 production from lung BAL cells and PBMCs of COPD patients.58 Recently, it was shown that IL-17 was expressed in the lymphocytes associated with tuberculosis (TB) granulomas and in the bronchoalveolar lavage fluid from patients with pulmonary TB.120 IL-17 drives airway stromal cell-derived matrix metalloproteinase-3, a mediator of tissue destruction in TB suggesting a possible role of RORc inhibitors in improving outcomes in TB therapy. In our opinion, RORc is a potential target for therapeutic interventions in autoimmune diseases through its inhibition or in cancer through its activation. Disclosure of additional clinical data will further strengthen the therapeutic potential of RORc inhibitors in diseases like psoriasis, MS and Crohn’s disease. The use of RORc inhibitors for respiratory indications and metabolic disorders is another area that requires attention. As a result, continued investigation into the discovery of new, selective RORc inhibitors and subsequent investigation in autoimmune disease models will contribute to future advances in the field. AUTHOR INFORMATION Corresponding Author *Phone: +912717665555. E-mail: [email protected] Notes


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The authors declare no competing financial interest. Biographies Vrajesh B. Pandya is a medicinal chemist at Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad, India. He obtained his Ph.D. degree from The Maharaja Sayajirao University of Baroda, Vadodara, India, studying novel compounds for the treatment of thrombotic and related disorders. He is actively involved in the discovery of new chemical entities in anti-inflammatory and anti-bacterial therapeutic areas. Sanjay Kumar is currently working as General Manager in Medicinal Chemistry department at Zydus Research Center, Ahmedabad India, where he is involved in preclinical drug discovery in various therapeutic areas viz., metabolic disorders, infectious diseases, etc. Prior to Zydus, he worked at Piramal Life Sciences Mumbai on Proliferative, Metabolic and Inflammatory disorders for a decade, and as a team delivered multiple clinical candidates to treat oncological and metabolic disorders. He obtained his Ph.D. degree from University of Allahabad and completed his postdoctoral research at Indian Institute of Science (IISc) Bangalore and Complex Carbohydrate Research Center (CCRC) University of Georgia at Athens USA. Sachchidanand is currently heading Bioinformatics Department at Zydus Research Center, Ahmedabad, India. Prior to Zydus, he worked as Associate Professor at NIPER Hajipur in the Department of Pharmacoinformatics, as Senior Scientist at Lupin Research Park, Pune in the Molecular Modeling Group and Senior Research Scientist at Institute of Life Sciences, Hyderabad. He obtained his D.Phil. degree from University of Oxford, UK and did his postdoctoral research at Mount Sinai School of Medicine, New York, USA. Rajiv Sharma is the senior vice president and head of chemistry at Zydus Research Center, Ahmedabad, where he is involved in the discovery and development of NCE’s in the field of



inflammation, anemia, and anti-bacterials for resistant infections. Dr. Sharma received his Ph.D. in organic chemistry from University of Delhi and obtained post-doctorate training in Medicinal chemistry in National Institutes of Health at Bethesda, Maryland. Prior to Zydus, he has worked in leadership positions at Piramal, Amgen, Tularik, and Boehringer Ingelheim. Ranjit C. Desai is a current Senior Consultant (Jan 2016-) and former Senior Vice President and Head of Chemistry for Zydus Research Center, Cadila Healthcare Ltd in Ahmedabad, India. Dr. Desai has been with Zydus since July, 2012 and during his tenure has led the development of four IND candidates in various therapeutic areas, ranging from the metabolic diseases to pain and oncology. In his current role with Zydus, he runs projects in the anti-infective area. Dr. Desai received his Ph.D. from the MS University of Baroda in Gujurat, India, where he worked with Dr. Sukh Dev at the Malti-Chem Research Centre. After working as a post-doctoral associate at Clemson University, Purdue University and University of Montreal, he held roles at SanofiWinthrop, Hoechst Celanese, and Merck Research Laboratories.

ACKNOWLEDGMENTS We thank Dr. Amit Joharapurkar and Mr. Jeevan Kumar for their help in preparing manuscript. ABBREVIATIONS USED AF, activation function helix; ARE, antioxidant response element; AS, ankylosing spondylitis; CIA, collagen-induced arthritis; CNS, central nervous system; COPD, chronic obstructive pulmonary disease; EAE, experimental autoimmune encephalomyelitis; FRET, fluorescence resonance energy transfer; Fsp3, fraction of saturated carbons; GM-CSF, granulocytemacrophage colony stimulating factor; HLM, human liver microsome; HTS, high throughput


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screening; IBD, inflammatory bowel disease; IL, interleukin; ILC, innate lymphoid cells; IMQ, Imiquimod; LBD, ligand-binding domain; LBP, ligand-binding pocket; LE, ligand efficiency; LTi, lymphoid tissue inducer; LXR, liver X receptor; MAD multiple ascending dose; MI, myocardial infarction; MS, multiple sclerosis; NR, nuclear receptor; NRF2, nuclear factor erythroid-derived 2-related factor 2; PASI, psoriasis area severity index; PBMC, peripheral blood mononuclear cell; PDB, protein data bank; PK, pharmacokinetics; PPAR, peroxisome proliferator-activated receptor; PXR, pregnane X receptor; RA, rheumatoid arthritis; RARγ, retinoic acid receptor gamma; RLM, rat liver microsome; ROR, retinoic acid receptor-related orphan receptor; SAD, single ascending dose; SAR, structure-activity relationship; SPA, scintillation proximity assay; SRC, steroid receptor coactivator; TB, tuberculosis; Tc, cytotoxic T cell; Th, T helper cell; Treg, regulatory T cells.

REFERENCES (1) Balagué, C.; Kunkel, S. L.; Godessart, N. Understanding autoimmune disease: new targets for drug discovery. Drug Discov. Today 2009, 14, 926-934. (2) Campa, M.; Mansouri, B.; Warren, R.; Menter, A. A review of biologic therapies targeting IL-23 and IL-17 for use in moderate-to-severe plaque psoriasis. Dermatol Ther (Heidelb), 2016, 6, 1–12.



(3) Balato, A.; Scala, E.; Balato, N.; Caiazzo, G.; Caprio, R. D.; Monfrecola, G.; Raimondo, A.; Lembo, S.; Ayala, F. Biologics that inhibit the Th17 pathway and related cytokines to treat inflammatory disorders. Expert Opin. Biol. Ther 2017, 17, 1363-1374. (4) Maxwell, J. R.; Zhang,Y.; Brown, W. A.; Smith, C. L.; Byrne, F. R.; Fiorino, M.; Stevens, E.; Bigler, J.; Davis, J. A.; Rottman, J. B.; Budelsky, A. L.; Symons, A.; Towne, J. E. Differential roles for interleukin-23 and interleukin-17 in intestinal immunoregulation. Immunity 2015, 43, 739-750. (5) Ivanov, I. I.; McKenzie, B. S.; Zhou, L.; Tadokoro, C. E.; Lepelley, A.; Lafaille, J. J.; Cua, D. J.; Littman, D. R. The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 2006, 126, 1121-1133. (6) Xiao, S.; Yosef, N.; Yang, J.; Wang, Y.; Zhou, L.; Zhu, C,; Wu, C.; Baloglu, E.; Schmidt, D.; Ramesh, R.; Lobera, M.; Sundrud, M. S.; Tsai, P. Y.; Xiang, Z.; Wang, J.; Xu, Y.; Lin, X.; Kretschmer, K.; Rahl, P. B.; Young, R. A.; Zhong, Z.; Hafler, D. A.; Regev, A.; Ghosh, S.; Marson, A.; Kuchroo, V. K. Small molecule RORγt antagonists inhibit T helper 17 cell transcriptional network by divergent mechanisms. Immunity 2014, 40, 477-489. (7) Castro, G.; Liu, X.; Ngo, K.; De Leon-Tabaldo, A.; Zhao, S.; Luna-Roman, R.; Yu, J.; Cao, T.; Kuhn, R.; Wilkinson, P.; Herman, K.; Nelen, M. I.; Blevitt, J.; Xue, X.; Fourie, A.; FungLeung, W. P. RORγt and RORα signature genes in human Th17 cells. PLoS One 2017, 12, e0181868. (8) Fauber, B. P.; Magnuson, S. Modulators of the nuclear receptor retinoic acid receptor-related orphan receptor-γ (RORγ or RORc). J. Med. Chem. 2014, 57, 5871−5892. (9) Jetten, A. M. Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism. Nucl Recept Signal 2009, 7, e003.


Page 40 of 67

Page 41 of 67 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(10)

Xue, X.; Soroosh, P.; Leon-Tabaldo, A. D.; Luna-Roman, R.; Sablad, M.; Rozenkrants,

N.; Yu, J.; Castro, G.; Banie, H.; Fung-Leung, W-P.; Santamaria-Babi, L.; Schlueter, T.; Albers, M.; Leonard, K.; Budelsky, A. L. Fourie, A. M. Pharmacologic modulation of RORγt translates to efficacy in preclinical and translational models of psoriasis and inflammatory arthritis. Sci. Rep. 2016, 6, 37977. (11)

Chang, M. R.; He, Y.; Khan, T. M.; Kuruvilla, D. S.; Garcia-Ordonez, R.; Corzo, C. A.;

Unger, T. J.; White, D. W.; Khan, S.; Lin, L.; Cameron, M. D.; Kamenecka, T. M.; Griffin, P. R. Antiobesity effect of a small molecule repressor of RORγ. Mol Pharmacol. 2015, 88, 48-56. (12)

Sun, Z.; Unutmaz, D.; Zou, Y.-R.; Sunshine, M. J.; Pierani, A.; Brenner-Morton, S.;

Mebius, R. E.; Littman, D. R. Requirement of RORγ in thymocyte survival and lymphoid organ development. Science 2000, 288, 2369−2373. (13)

Eberl, G.; Marmon, S.; Sunshine, M.-J.; Rennert, P. D.; Choi, Y.; Littman, D. R. An

essential function for the nuclear receptor RORγt in the generation of fetal lymphoid tissue inducer cells. Nat. Immunol. 2004, 5, 64−73. (14)

Kurebayashi, S.; Ueda, E.; Sakaue, M.; Patel, D. D.; Medvedev, A.; Zhang, F.; Jetten, A.

M. Retinoid-related orphan receptor γ (RORγ) is essential for lymphoid organogenesis and controls apoptosis during thymopoiesis. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 10132−10137. (15)

Enomoto, D.; Matsumoto, K.; Yamashita, T.; Kobayashi, A.; Maeda, M.; Nakayama, H.;

Obana, M.; Fujio, Y. RORγt-expressing cells attenuate cardiac remodeling after myocardial infarction. PLoS One 2017, 12, e0183584.



(16)

Page 42 of 67

Jin, L.; Martynowski, D.; Zheng, S.; Wada, T.; Xie, W.; Li, Y. Structural basis for

hydroxycholesterols a natural ligands of orphan nuclear receptor RORγ. Mol. Endocrinol. 2010, 24, 923−929. (17)

Kallen, J.; Izaac, A.; Be, C.; Arista, L.; Orain, D.; Kaupmann, K.; Guntermann, C.;

Hoegenauer, K.; Hintermann, S. Structural states of RORγt: X-ray elucidation of molecular mechanisms and binding interactions for natural and synthetic compounds. ChemMedChem. 2017, 12, 1014-1021. (18)

VitaePharmaceuticals.https://clinicaltrials.gov/ct2/show/NCT02555709?term=VTP43742

&rank=1 (accessed March 13, 2018). (19)

GlaxoSmithKline.https://clinicaltrials.gov/ct2/show/NCT03004846?term=GSK2981278

&rank=1 (accessed March 13, 2018). (20)

ArrienPharmaceuticals.https://clinicaltrials.gov/ct2/show/NCT03237832?term=ARN-

6039&rank=1(accessed March 13, 2018). (21)

Takeda.https://clinicaltrials.gov/ct2/show/NCT02706834?term=TAK828&rank=2

(accessed March 13, 2018). (22)

AbbVie.https://clinicaltrials.gov/ct2/show/NCT03145948?term=ABBV-553&rank=1


Phenex

Pharmaceuticals

AG

press

release.

http://www.phenex-

pharma.com/pdf/Phenex_Janssen_Ph1_eng_2017_final.pdf. Accessed on July 10, 2017. (24)

AstraZeneca. https://clinicaltrials.gov/ct2/show/NCT03310320?term=AZD-0284&rank=1


AkrosPharma(subsidiaryofJapanTobacco).https://clinicaltrials.gov/ct2/show/NCT030185

09?term=JTE-451&rank=1 (accessed March 13, 2018).


Page 43 of 67 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(26)

Japan

Tobacco

Inc.

clinical

development

as

of

July

30,

2013.

http://www.jtcom/investors/results/S_information/pharmaceuticals/pdf/P.L.20130730_E.pdf. (27)

Reata

Pharmaceuticals.

http://investors.reatapharma.com/news-releases/news-release-

details/reata-announces-initiation-phase-1-trial-rta-1701-selective-oral. (28)

Bronner, S. M.; Zbieg, J. R.; Crawford, J. J. RORγ antagonists and inverse agonists: a

patent review. Expert Opin Ther Pat. 2017, 27(1), 101-112. (29)

Kamenecka, T. M.; Lyda, B.; Chang, M. R.; Griffin, P. R. Synthetic modulators of the

retinoic acid receptor-related orphan receptors. Med. Chem. Commun. 2013, 4, 764-776. (30)

Cyr, P.; Bronner, S. M.; Crawford, J. J.; Recent progress on nuclear receptor RORc

modulators. Bioorg Med Chem Lett. 2016, 26, 4387-4393. (31)

Qiu, R.; Wang, Y. Retinoic acid receptor-related orphan receptor γt (RORγt) agonists as

potential small molecule therapeutics for cancer immunotherapy. J. Med. Chem. [Online early access]. DOI: 10.1021/acs.jmedchem.7b01314. Published Online: Feb 7, 2018. (32)

Kumar, N.; Solt, L. A.; Conkright, J. J.; Wang, Y.; Istrate, M. A.; Busby, S. A.; Garcia-

Ordonez, R. D.; Burris, T. P.; Griffin, P. R. The benzenesulfonamide T0901317 [N-(2,2,2trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-(trifluoromethyl)ethyl]phenyl] benzenesulfonamide] is a novel retinoic acid receptor-related orphan receptor-α/γ inverse agonist. Mol. Pharmacol. 2010, 77, 228−236. (33)

Kumar, N.; Lyda, B.; Chang, M. R.; Lauer, J. L.; Solt, L. A.; Burris, T. P.; Kamenecka,

T. M.; Griffin, P. R. Identification of SR2211: a potent synthetic RORγ-selective modulator. ACS Chem. Biol. 2012, 7, 672−677.



(34)

Solt, L. A.; Kumar, N.; He, Y.; Kamenecka, T. M.; Griffin, P. R.; Burris, T. P.

Identification of a selective RORγ ligand that suppresses TH17 cells and stimulates Tregulatory cells. ACS Chem. Biol. 2012, 7, 1515−1519. (35)

Chang, M. R.; Lyda, B.; Kamenecka, T. M.; Griffin, P. R. Pharmacological repression of

RORγ is therapeutic in the collagen-induced arthritis experimental model. Arthritis Rheum. 2014, 66, 579-588. (36)

Fauber, B. P.; de Leon Boenig, G.; Burton, B.; Eidenschenk, C.; Everett, C.; Gobbi,

Alberto; Hymowitz, S. G.; Johnson, A.; Limatta, M.; Lockey, P.; Norman, M.; Ouyang, W.; René, O.; Wong, H. Structure-based design of substituted hexafluoroisopropanolarylsulfonamides as modulators of RORc. Bioorg. Med. Chem. Lett. 2013, 23, 6604−6609. (37)

Gong, H.; Weinstein, D. S.; Lu, Z.; Duan, J. J.; Stachura, S.; Haque, L.; Karmakar, A.;

Hemagiri, H.; Raut, D. K.; Gupta, A. K.; Khan, J.; Camac, D.; Sack, J. S.; Pudzianowski, A.; Wu, D. R.; Yarde, M.; Shen, D. R.; Borowski, V.; Xie, J. H.; Sun, H.; D'Arienzo, C.; Dabros, M.; Galella, M. A.; Wang, F.; Weigelt, C. A.; Zhao, Q.; Foster, W.; Somerville, J. E.; SalterCid, L. M.; Barrish, J. C.; Carter, P. H.; Murali Dhar, T. G. Identification of bicyclic hexafluoroisopropyl alcohol sulfonamides as retinoic acid receptor-related orphan receptor gamma (RORγ/RORc) inverse agonists. Employing structure-based drug design to improve pregnane X receptor (PXR) selectivity. Bioorg Med Chem Lett. 2018, 28, 85-93. (38)

Fauber, B. P.; Gobbi, A.; Savy, P.; Burton, B.; Deng, Y.; Everett, C.; La, H.; Johnson, A.

R.; Lockey, P.; Norman, M.; Wong, H. Identification of N-sulfonyl-tetrahydroquinolines as RORc inverse agonists. Bioorg Med Chem Lett. 2015, 25, 4109-4113. (39)

Olsson, R. I.; Xue, Y.; von Berg, S.; Aagaard, A.; McPheat, J.; Hansson, E. L.;

Bernström, J.; Hansson, P.;, Jirholt, J.; Grindebacke, H.; Leffler, A.; Chen, R.; Xiong, Y.; Ge,


Page 44 of 67

Page 45 of 67 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


H.; Hansson, T. G.; Narjes, F. Benzoxazepines achieve potent suppression of IL-17 release in human T-helper 17 (TH17) cells through an induced-fit binding mode to the nuclear receptor RORγ. ChemMedChem. 2016, 11, 207-216. (40)

Fauber, B. P.; René, O.; de Leon Boenig, G.; Burton, B.; Deng, Y.; Eidenschenk, C.;

Everett, C.; Gobbi, A.; Hymowitz, S. G.; Johnson, A. R.; La, H.; Liimatta, M.; Lockey, P.; Norman, M.; Ouyang, W.; Wang, W.; Wong, H. Reduction in lipophilicity improved the solubility, plasma-protein binding, and permeability of tertiary sulfonamide RORc inverse agonists. Bioorg Med Chem Lett. 2014, 24, 3891-3897. (41)

René, O.; Fauber, B. P.; Boenig, G-L.; Burton, B.; Eidenschenk, C.; Everett, C.; Gobbi,

A.; Hymowitz, S. G.; Johnson, A. R.; Kiefer, J. R.; Liimatta, M.; Lockey, P.; Norman, M.; Ouyang, W.; Wallweber, H. A.; Wong, H. Minor structural change to tertiary sulfonamide RORc ligands led to opposite mechanisms of action. ACS Med. Chem. Lett. 2015, 6, 276−281. (42)

Fauber, B. P.; René, O.; Deng, Y.; DeVoss, J.; Eidenschenk, C.; Everett, C.; Ganguli, A.;

Gobbi, A.; Hawkins, J.; Johnson, A. R.; La, H.; Lesch, J.; Lockey, P.; Norman, M.; Ouyang, W.; Summerhill, S.; Wong, H. Discovery of 1-{4-[3-fluoro-4-((3s,6r)-3-methyl-1,1-dioxo-6phenyl-[1,2]thiazinan-2-ylmethyl)-phenyl]-piperazin-1-yl}-ethanone (GNE-3500): a potent, selective, and orally bioavailable retinoic acid receptor-related orphan receptor C (RORc or RORγ) inverse agonist. J. Med. Chem. 2015, 58, 5308−5322. (43)

Bodil Van Niel, M.; Fauber, B.; Gaines, S.; Gobbi, A.; Rene, O.; Vesey, D.; Ward, S.

Aryl Sultam Derivatives as RORc Modulators. WO2014009447A1, 2014. (44)

Birault, V.; Campbell, A. J.; Harrison, S. A.; LE, J. Novel Compounds.

WO2015061515A1, 2015.



(45)

Page 46 of 67

Birault, V.; Campbell, A. J.; Harrison, S. A.; LE, J.; Shukla, L. Novel Compounds.

WO2013160418A1, 2013. (46)

Smith, S. H.; Peredo, C. E.; Takeda, Y.; Bui, T.; Neil, J.; Rickard, D.; Millerman, E.;

Therrien, J. P.; Nicodeme, E.; Brusq, J. M.; Birault, V.; Viviani, F.; Hofland, H.; Jetten, A. M.; Cote-Sierra, J. Development of a topical treatment for psoriasis targeting RORγ: From bench to skin. PLoS One 2016, 11, e0147979. (47)

Ouvry, G.; Atrux-Tallau, N.; Bihl, F.; Bondu, A.; Bouix-Peter, C.; Carlavan, I.; Christin,

O.; Cuadrado, M. J.; Defoin-Platel, C.; Deret, S.; Duvert, D.; Feret, C.; Forissier, M.; Fournier, J. F.; Froude, D.; Hacini-Rachinel, F.; Harris, C. S.; Hervouet, C.; Huguet, H.; Lafitte, G.; Luzy, A. P.; Musicki, B.; Orfila, D.; Ozello, B.; Pascau, C.; Pascau, J.; Parnet, V.; Peluchon, G.; Pierre, R.; Piwnica, D.; Raffin, C.; Rossio, P.; Spiesse, D.; Taquet, N.; Thoreau, E.; Vatinel, R.; Vial, E.; Hennequin, L. F. Discovery and characterization of CD12681, a potent RORγ inverse agonist, preclinical candidate for the topical treatment of psoriasis. ChemMedChem. 2018, 13, 321-337. (48)

Wang, Y.; Yang, T.; Liu, Q.; Ma, Y.; Yang, L.; Zhou, L.; Xiang, Z.; Cheng, Z.; Lu, S.;

Orband-Miller, L. A.; Zhang, W.; Wu, Q.; Zhang, K.; Li, Y.; Xiang, J-N.; Elliott, J. D.; Leung, S.; Ren, F.; Lin, Xichen. Discovery of N-(4-aryl-5-aryloxy-thiazol-2-yl)-amides as potent RORγt inverse agonists. Bioorg Med Chem. 2015, 23, 5293-5302. (49)

Wang, Y.; Cai, W.; Zhang, G.; Yang, T.; Liu, Q.; Cheng, Y.; Zhou, L.; Ma, Y.; Cheng,

Z.; Lu, S.; Zhao, YG.; Zhang, W.; Xiang, Z.; Wang, S.; Yang, L.; Wu, Q.; Orband-Miller, L. A.; Xu, Y.; Zhang, J.; Gao, R.; Huxdorf, M.; Xiang, J. N.; Zhong, Z.; Elliott, J. D.; Leung, S.; Lin,

X.

Discovery

of

novel

N-(5-(arylcarbonyl)thiazol-2-yl)amides


and

N-(5-

Page 47 of 67 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(arylcarbonyl)thiophen-2-yl)amides as potent RORγt inhibitors. Bioorg Med Chem. 2014, 22, 692-702. (50)

Gege, C.; Schlüter, T.; Hoffmann, T. Identification of the first inverse agonist of retinoid-

related orphan receptor (ROR) with dual selectivity for RORβ and RORγt. Bioorg Med Chem Lett. 2014, 24, 5265-5267. (51)

Wang, Y.; Cai, W.; Cheng, Y.; Yang, T.; Liu, Q.; Zhang, G.; Meng, Q.; Han, F.; Huang,

Y.; Zhou, L.; Xiang, Z.; Zhao, Y. G.; Xu, Y.; Cheng, Z.; Lu, S.; Wu, Q.; Xiang, J. N.; Elliott, J. D.; Leung, S.; Ren, F.; Lin, X. Discovery of biaryl amides as potent, orally bioavailable, and CNS penetrant RORγt inhibitors. ACS Med. Chem. Lett. 2015, 6, 787−792. (52)

Xiao, S.; Yosef, N.; Yang, J.; Wang, Y.; Zhou, L.; Zhu, C.; Wu, C.; Baloglu, E.; Schmidt,

D.; Ramesh, R.; Lobera, M.; Sundrud, M. S.; Tsai, P. Y.; Xiang, Z.; Wang, J.; Xu, Y.; Lin, X.; Kretschmer, K.; Rahl, P. B.;, Young, R. A.; Zhong, Z.; Hafler, D. A.; Regev, A.; Ghosh, S.; Marson, A.; Kuchroo, V. K. Small-molecule RORγt antagonists inhibit T helper 17 cell transcriptional network by divergent mechanisms. Immunity 2014, 40, 477-489. (53)

Wang, Y.; Cai, W.; Tang, T.; Liu, Q.; Yang, T.; Yang, L.; Ma, Y.; Zhang, G.; Huang, Y.;

Song, X.; Orband-Miller, L. A.; Wu, Q.; Zhou, L.; Xiang, Z.; Xiang, J. N.; Leung, S.; Shao, L.; Lin, X.; Lobera, M.; Ren, F. From RORγt agonist to two types of RORγt inverse agonists. ACS Med. Chem. Lett. 2018, 9, 120−124. (54)

Desai, R.; Kumar, S. S.; Pandya, V.; Desai, J.; Raval, S. Cyclopropyl Derivatives as

ROR-gamma Modulators. WO2018011746A1, 2018. (55)

Zhuang, L. Discovery of VTP-43742, a RORγt inverse agonist for the treatment of

psoriasis. 13th winter conference on medicinal and bioorganic chemistry, Steamboat Springs, CO. January 22-26, 2017.



(56)

McGeehan, G. M. The RORγt blocker, VTP-43742, suppresses Th17 activity providing

greater benefit than IL-17A blockade in an EAE model of autoimmunity. Poster presented at Keystone Symposia on Mechanisms of Pro-Inflammatory Diseases. 23rd April 2015. http://www.keystonesymposia.org/15Z4. (57)

Claremon, D. A.; Dillard, L. W.; Dong, C.; Fan, Y.; Jia, L.; Lotesta, S. D.; Marcus, A.;

Singh, S. B.; Tice, C. M.; Yuan, J.; Zhao, W.; Zheng, Y.; Zhuang, L. Dihydropyrrolopyridine Inhibitors of ROR-gamma. WO2016061160A1, 2016. (58)

Khairatkar-Joshi, N.; Kulkarni, A.; Shah, D. M.; Bhosale, V. M.; Lodhiya, B. J.;

Thiraviam, A. M.; Marathe, M.; Hadambar, A. A. Treatment of Respiratory Disorders Using ROR-gamma Inhibitors. WO2016193894A1, 2016. (59)

Morphy, J. R. Compounds Useful For Inhibiting ROR-Gamma-T. WO2017044410A1,

2017. (60)

Lever, S.; Narjes, F.; Olsson, R. I.; Von Berg, S. Isoindole Compounds.

WO2017102784A1, 2017. (61)

Narjes, F. The discovery of AZD0284, an inverse agonist of the nuclear receptor RORγ.

American chemical society, Drug design and delivery symposium, October 26, 2017. https://www.acs.org/content/acs/en/acs-webinars/drug-discovery/psoriasis.html. (62)

Brunette, S. R.; Csengery, J.; Hughes, R. O.; Li, X.; Sibley, R.; Turner, M. R.; Xiong, Z.

Pteridine Derivatives as Modulators of ROR Gamma. WO2017058831A1, 2017. (63)

Chao, J.; Enyedy, I.; Vloten, K. V.; Marcotte, D.; Guertin, K.; Hutchings, R.; Powell, N.;

Jones, H.; Bohnert, T.; Peng, C. C.; Silvian, L.; Hong, V. S.; Little, K.; Banerjee, D.; Peng, L.; Taveras, A.; Viney, J. L.; Fontenot, J. Discovery of biaryl carboxylamides as potent RORγ inverse agonists. Bioorg Med Chem Lett. 2015, 25, 2991-2997.


Page 48 of 67

Page 49 of 67 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(64)

Wang, T.; Banerjee, D.; Bohnert, T.; Chao, J.; Enyedy, I.; Fontenot, J.; Guertin, K.;

Jones, H.; Lin, E. Y.; Marcotte, D.; Talreja, T.; Vloten, K. V. Discovery of novel pyrazolecontaining benzamides as potent RORγ inverse agonists. Bioorg Med Chem Lett. 2015, 25, 2985-2990. (65)

Han, F.; Lei, H.; Lin, X.; Meng, Q.; Wang, Y. Modulators of The Retinoid-Related

Orphan Receptor Gamma (ROR-Gamma) For Use in The Treatment of Autoimmune And Inflammatory Diseases. WO2014086894A1, 2014. (66)

Guntermann, C.; Piaia, A.; Hamel, M. L.; Theil, D.; Rubic-Schneider, T.; Del Rio-

Espinola, A.; Dong, L.; Billich, A.; Kaupmann, K.; Dawson, J.; Hoegenauer, K.; Orain, D.; Hintermann, S.; Stringer, R.; Patel, D. D.; Doelemeyer, A.; Deurinck, M.; Schümann, J. Retinoic-acid-orphan-receptor-C inhibition suppresses Th17 cells and induces thymic aberrations. JCI Insight. 2017, 2, e91127. (67)

Hintermann, S.; Guntermann, C.; Mattes, H.; Carcache, D. A.; Wagner, J.; Vulpetti, A.;

Billich, A.; Dawson, J.; Kaupmann, K.; Kallen, J.; Stringer, R.; Orain, D. Synthesis and biological evaluation of new triazolo- and imidazolopyridine RORγt inverse agonists. ChemMedChem. 2016, 11, 2640-2648. (68)

Takaishi, M.; Ishizaki, M.; Suzuki, K.; Isobe, T.; Shimozato, T.; Sano, S. Oral

administration of a novel RORγt antagonist attenuates psoriasis-like skin lesion of two independent mouse models through neutralization of IL-17. J Dermatol Sci. 2017, 85, 12-19. (69)

Flick, A. C.; Jones, P.; Kaila, N.; Mente, S. R.; Schnute, M. E.; Trzupek, J. D.; Vazquez,

M. L.; Xing, L.; Zhang, L.; Wennerstål, G. M.; Zamaratski, E. Methyl-And TrifluoromethylSubstituted Pyrrolopyridine Modulators of RORC2 and Methods of Use Thereof. WO2016046755A1, 2016.



(70)

Kono, M.; Oda, T.; Tawada, M.; Imada, T.; Banno, Y.; Taya, N.; Kawamoto, T.;

Tokuhara, H.; Tomata, Y.; Ishii, N.; Ochida, A.; Fukase, Y.; Yukawa, T.; Fukumoto, S.; Watanabe, H.; Uga, K.; Shibata, A.; Nakagawa, H.; Shirasaki, M.; Fujitani, Y.; Yamasaki, M.; Shirai, J.; Yamamoto S. Discovery of orally efficacious RORγt inverse agonists. Part 2: Design, synthesis, and biological evaluation of novel tetrahydroisoquinoline derivatives. Bioorg Med Chem. 2018, 26, 470-482. (71)

Yamamoto, S.; Shirai, J.; Fukase, Y.; Tomata, Y.; Sato, A.; Ochida, A.; Yonemori, K.;

Nakagawa, H. Condensed Heterocyclic Compound. WO 2013042782A1, 2013. (72)

Shirai, J.; Tomata, Y.; Kono, M.; Ochida, A.; Fukase, Y.; Sato, A.; Masada, S.;

Kawamoto, T.; Yonemori, K.; Koyama, R.; Nakagawa, H.; Nakayama, M.; Uga, K.; Shibata, A.; Koga, K.; Okui, T.; Shirasaki, M.; Skene, R.; Sang, B.; Hoffman, I.; Lane, W.; Fujitani, Y.; Yamasaki, M.; Yamamoto, S. Discovery of orally efficacious RORγt inverse agonists, part 1: Identification of novel phenylglycinamides as lead scaffolds. Bioorg Med Chem. 2018, 26, 483-500. (73)

Toyama, H.; Nakamura, M.; Nakamura, M.; Matsumoto, Y.; Nakagomi, M.; Hashimoto,

Y. Development of novel silicon-containing inverse agonists of retinoic acid receptor-related orphan receptors. Bioorg Med Chem. 2014, 22, 1948-1959. (74)

Kono, M.; Ochida, A.; Oda, T.; Imada, T.; Banno, Y.; Taya, N.; Masada, S.; Kawamoto,

T.; Yonemori, K.; Nara, Y.; Fukase, Y.; Yukawa, T.; Tokuhara, H.; Skene, R.; Sang, B. C.; Hoffman, I. D.; Snell, G. P.; Uga, K.; Shibata, A.; Igaki, K.; Nakamura, Y.; Nakagawa, H.; Tsuchimori, N.; Yamasaki, M.; Shirai, J.; Yamamoto, S. Discovery of [cis-3-({(5R)-5-[(7fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl]-2-methoxy-7,8-dihydro-1,6naphthyridin-6(5H)-yl}carbonyl)cyclobutyl]acetic acid (TAK-828F) as a potent, selective,


Page 50 of 67

Page 51 of 67 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


and orally available novel retinoic acid receptor-related orphan receptor γt inverse agonist. J. Med. Chem. 2018, 61, 2973-2988. (75)

Shibata, A.; Uga, K.; Sato, T.; Sagara, M.; Igaki, K.; Nakamura, Y.; Ochida, A.; Kono,

M.; Shirai, J.; Yamamoto, S.; Yamasaki, M.; Tsuchimori, N. Pharmacological inhibitory profile of TAK-828F, a potent and selective orally available RORγt inverse agonist. Biochem Pharmacol. 2018, 150, 35-45. (76)

Takeda. https://www.takeda.com/investors/reports/quarterly-announcements/. FY2016

full year results (released on May 10, 2017), Data Book. (accessed March 26, 2018). (77)

Hirata, K.; Kotoku, M.; Seki, N.; Maeba, T.; Maeda, K.; Hirashima, S.; Sakai, T.; Obika,

S.; Hori, A.; Hase, Y.; Yamaguchi, T.; Katsuda, Y.; Hata, T.; Miyagawa, N.; Arita, K.; Nomura, Y.; Asahina, K.; Aratsu, Y.; Kamada, M.; Adachi, T.; Noguchi, M.; Doi, S.; Crowe, P.; Bradley, E.; Steensma, R.; Tao, H.; Fenn, M.; Babine, R.; Li, X.; Thacher, S.; Hashimoto, H.; Shiozaki, M. SAR exploration guided by LE and Fsp3: Discovery of a selective and orally efficacious RORγ Inhibitor. ACS Med. Chem. Lett. 2016, 7, 23−27. (78)

Scheepstra, M.; Leysen, S.; van Almen, G. C.; Miller, J. R.; Piesvaux, J.; Kutilek, V.; van

Eenennaam, H.; Zhang, H.; Barr, K.; Nagpal, S.; Soisson, S. M.; Kornienko, M.; Wiley, K.; Elsen, N.; Sharma, S.; Correll, C. C.; Trotter, B. W.; van der Stelt, M.; Oubrie, A.; Ottmann, C.; Parthasarathy, G.; Brunsveld, L. Identification of an allosteric binding site for RORγt inhibition. Nat Commun. 2015, 6, 8833. (79)

de Wit, J.; Al-Mossawi, M. H.; Huhn, M. H.; Arancibia-Carcamo, C. V.; Doig, K.;

Kendrick, B.; Gundle, R.; Taylor, P.; McClanahan, T.; Murphy, E.; Zhang, H.; Barr, K.; Miller, J. R.; Hu, X.; Aicher, T. D.; Morgan, R. W.; Glick, G. D.; Zaller, D.; Correll, C.;



Page 52 of 67

Powrie, F.; Bowness, P. J. RORγt inhibitors suppress T(H)17 responses in inflammatory arthritis and inflammatory bowel disease. J Allergy Clin Immunol. 2016, 137, 960-963. (80)

Zhang, H.; Barr, K. J.; Lapointe, B. T.; Gunaydin, H.; Liu, K.; Trotter, B. W. Heteroaryl

Substituted

Benzoic

Acids

as

RORgammaT

Inhibitors

and

Uses

Thereof.

WO2017075185A1, 2017. (81)

Fauber, B. P.; Gobbi, A.; Robarge, K.; Zhou, A.; Barnard, A.; Cao, J.; Deng, Y.;

Eidenschenk, C.; Everett, C.; Ganguli, A.; Hawkins, J.; Johnson, A. R.; La, H.; Norman, M.; Salmon, G.; Summerhill, S.; Ouyang, W.; Tang, W.; Wong, H. Discovery of imidazo[1,5a]pyridines and -pyrimidines as potent and selective RORc inverse agonists. Bioorg Med Chem Lett. 2015, 25, 2907-2912. (82)

Ouvry, G.; Bouix-Peter, C.; Ciesielski, F.; Chantalat, L.; Christin, O.; Comino, C.;

Duvert, D.; Feret, C.; Harris, C. S.; Lamy, L.; Luzy, A. P.; Musicki, B.; Orfila, D.; Pascau, J.; Parnet, V.; Perrin, A.; Pierre, R.; Polge, G.; Raffin, C.; Rival, Y.; Taquet, N.; Thoreau, E.; Hennequin, L. F. Discovery of phenoxyindazoles and phenylthioindazoles as RORγ inverse agonists. Bioorg Med Chem Lett. 2016, 26, 5802-5808. (83)

Skepner, J.; Ramesh, R.; Trocha, M.; Schmidt, D.; Baloglu, E.; Lobera, M.; Carlson, T.;

Hill, J.; Orband-Miller, L. A.; Barnes, A.; Boudjelal, M.; Sundrud, M.; Ghosh, S.; Yang, J. Pharmacologic inhibition of RORγt regulates Th17 signature gene expression and suppresses cutaneous inflammation in vivo. J Immunol. 2014, 192, 2564-2575. (84)

Gaweco, A.; Tilley, J.; Blinn, J. Sulfonamide Retinoic Acid Receptor-Related Orphan

Receptor Modulators And Uses. WO2016014910A1, 2016. (85)

Gaweco, A.; Tilley, J.; Blinn, J. Azaindole Retinoic Acid Receptor-Related Orphan

Receptor Modulators And Uses. WO2016014916A1, 2016.


Page 53 of 67 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(86)

Gaweco, A.; Tilley, J.; Blinn, J. Indazole Retinoic Acid Receptor-Related Orphan

Receptor Modulators And Uses. WO2016014913A1, 2016. (87)

Gaweco, A.; Adam, K.; Herbin, O.; Tilley, J. Therapeutic efficacy of a promising oral

INV-17 ROR gamma inverse agonist clinical lead compound in a mouse IMQ-psoriasis model. J Am Acad Dermatol. 2017, 76, AB259. (88)

https://nuevolution.com/almirall-and-nuevolution-enter-into-a-strategic-collaboration.

(89)

Schröder Glad, S.; Birkebäk Jensen, K.; Grön Nörager, N.; Sarvary, I.; Vestergaard, M.;

Haahr Gouliaev, A.; Teuber, L.; Stasi, L. P. Optionally Fused Heterocyclyl-Sustituted Derivatives of Pyrimidine Useful For the Treatment of Inflammatory, Metabolic, Oncologic And Autoimmune Diseases. WO2016020295A1, 2016. (90)

Nuss, J.; Harris, J.; Mohan, R. ROR-Gamma Modulators. WO2018081558A1, 2018.

(91)

Vankayalapati, H.; Yerramreddy, V. Substituted 2,3-Dihydro-1H-Inden-1-one Retinoic

Acid-Related Orphan Nuclear Receptor Antagonists For Treating Multiple Sclerosis. WO2015038350A2, 2015. (92)

Rose, J. W.; Carlson, N. G.; Yerramreddy, V.; Appalaneni, R. P.; Handler, J. A.;

Kancherla, R. R.; Vankayalapati, H. Discovery of ARN-6039 as a potent, orally available inverse agonist of RORγt for autoimmune neuroinflammatory demyelinating disease. Poster presented at the 68th AAN (American Academy of Neurology) Annual Meeting on April 1521,

2016.

Available

from:

https://tools.aan.com/annualmeeting/search/index.cfm?fuseaction=home.detail&id=5109&ke yword=&topic=81&type=all.



(93)

Argiriadi, M. A.; Breinlinger, E.; Cusack, K. P.; Hobson, A. D.; Potin, D.; Barth, M.;

Amaudrut, J.; Poupardin, O.; Mounier, L.; Kort, M. E. ROR Nuclear Receptor Modulators. WO2016198908A1, 2016. (94)

Fauber, B.; Bodil Van Niel, M.; Cridland, A.; Hurley, C.; Killen, J.; Ward, S. Pyridazine

Derivatives As RORc Modulators. WO2016177686A1, 2016. (95)

Steeneck, C.; Kinzel, O.; Gege, C.; Kleymann, G.; Hoffmann, T. Pyrrolo Carboxamides

As Modulators of Orphan Nuclear Receptor RAR-Related Orphan Receptor-Gamma (RORγ, NR1F3) Activity And For the Treatment of Chronic Inflammatory And Autoimmune Diseases. WO2013079223A1, 2013. (96)

Gege, C.; Steeneck, C.; Kinzel, O.; Kleymann, G.; Hoffmann, T. Carboxamide or

Sulfonamide Substituted Thiazoles and Related Derivatives as Modulators For the Orphan Nuclear Receptor ROR[Gamma]. WO2013178362A1, 2013. (97)

Gege, C.; Kinzel, O.; Steeneck, C.; Kleymann, G.; Hoffmann, T. Carboxamide or

Sulfonamide Substituted Nitrogen-Containing 5-Membered Heterocycles as Modulators For the Orphan Nuclear Receptor ROR Gamma. WO2014023367A1, 2014. (98)

Gege, C.; Cummings, M. D.; Albers, M.; Kinzel, O.; Kleymann, G.; Schluter, T.;

Steeneck, C.; Nelen, M. I.; Milligan, C.; Spurlino, J.; Xue, X.; Leonard, K.; Edwards, J. P.; Fourie, A.; Goldberg, S. D.; Hoffmann, T.

Identification and biological evaluation of

thiazole-based inverse agonists of RORγt. Bioorg Med Chem Lett. 2018, 28, 1446-1455. (99)

Mcclure, K.; Tanis, V. M.; Fennema, E. G.; Lebsack, A. D.; Martin, C. L.; Venkatesan,

H.; Xue, X.; Woods, C. R. 6-Aminopyridin-3-yl Thiazoles as Modulators of RORγt. WO2017189661A1, 2017.


Page 54 of 67

Page 55 of 67 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(100) Barbay, K.; Edwards, J. P.; Kreutter, K. D.; Kummer, D. A.; Maharoof, U.; Nishimura, R.; Urbanski, M.; Venkatesan, H.; Wang, A.; Wolin, R. L.; Woods, C. R.; Fourie, A.; Xue, X.; Cummings, M. D.; Leonard, K. A. Phenyl Linked Quinolinyl Modulators of RORGamma-T. WO2015057203A1, 2015. (101) Barbay, K.; Edwards, J. P.; Kreutter, K. D.; Kummer, D. A.; Maharoof, U.; Nishimura, R.; Urbanski, M.; Venkatesan, H.; Wang, A.; Wolin, R. L.; Woods, C. R.; Fourie, A.; Xue, X.; Cummings, M. D.; Jones, W. M.; Goldberg, S. Methylene Linked Quinolinyl Modulators of ROR-Gamma-T. WO2015057205A1, 2015. (102) Barbay, K.; Edwards, J. P.; Kreutter, K. D.; Kummer, D. A.; Maharoof, U.; Nishimura, R.; Urbanski, M.; Venkatesan, H.; Wang, A.; Wolin, R. L.; Woods, C. R.; Fourie, A.; Xue, X.;

Cummings,

M.

D.

Secondary

Alcohol

Quinolinyl

Modulators

of

RORγt.

WO2015057206A1, 2015. (103) Barbay, K.; Edwards, J. P.; Kreutter, K. D.; Kummer, D. A.; Maharoof, U.; Nishimura, R.; Urbanski, M.; Venkatesan, H.; Wang, A.; Wolin, R. L.; Woods, C. R.; Fourie, A.; Xue, X.; Cummings, M. D.; Mcclure, K.; Tanis, V. Quinolinyl Modulators of RORγt. WO2015057626A1, 2015. (104) Barbay, J. K.; Cummings, M. D.; Abad, M.; Castro, G.; Kreutter, K. D.; Kummer, D. A.; Maharoof, U.; Milligan, C.; Nishimura, R.; Pierce, J.; Schalk-Hihi, C.; Spurlino, J.; Tanis, V. M.; Urbanski, M.; Venkatesan, H.; Wang, A.; Woods, C.; Wolin, R.; Xue, X.; Edwards, J. P.; Fourie, A. M.; Leonard, K. 6-Substituted quinolines as RORγt inverse agonists. Bioorg Med Chem Lett. 2017, 27, 5277-5283. (105) ReataPharmaceuticals.http://www.jimmunol.org/content/200/1_Supplement/121.14?utm_ source=TrendMD&utm_medium=cpc&utm_campaign=J_Immunol_TrendMD_0.



Page 56 of 67

(106) Reata Pharmaceuticals.http://www.jimmunol.org/content/200/1_Supplement/175.22. (107) Visnick, M.; Jiang, X.; Hotema, M. R.; Lee, C.; Caprathe, B. W.; Roark, W. H.; Bolton, G. C4-Modified Oleanolic Acid Derivatives For Inhibition of IL-17 And Other Uses. WO2017053868A1, 2017. (108) Chin, M. P.; Bakris, G. L.; Block, G. A.; Chertow, G. M.; Goldsberry, A.; Inker, L. A.; Heerspink, H. J. L.; O'Grady, M.; Pergola, P. E.; Wanner, C.; Warnock, D. G.; Meyer, C. J. Bardoxolone methyl improves kidney function in patients with chronic kidney disease stage 4 and type 2 diabetes: Post-hoc analyses from bardoxolone methyl evaluation in patients with chronic kidney disease and type 2 diabetes study. Am J Nephrol. 2018, 47, 40-47. (109) Jiang, X.; Bender, C. F.; Visnick, M.; Hotema, M. R.; Sheldon, Z. S.; Lee, C.; Caprathe, B. W.; Bolton, G.; Kornberg, B. Pyrimidine Tricyclic Enone Derivatives For Inhibition of RORγ And Other Uses. WO2018111315A1, 2018. (110) McGeehan, G. M.; Palmer, S. A.; Bryson, C. C.; Zhao, Y.; Shi, M.; Lipinski, K. K.; Bukhtiyarov, Y.; Guo, J.; Claremon, D. A.; Lala, D. S.; Gregg, R. E. Safety, tolerability, pharmacokinetics and pharmacodynamics of VTP-43742, a RORγt antagonist, in healthy volunteers.

Poster

presented

at

IMMUNOLOGY

2016.

http://www.jimmunol.org/content/196/1_Supplement/71.4. (111) Vitae

Pharmaceuticals.

http://ir.vitaepharma.com/phoenix.zhtml?c=219654&p=irol-

newsArticle&ID=2149044. (accessed March 26, 2018). (112) https://seekingalpha.com/news/3350282-allergan-writes-lead-candidate-640m-vitae-buyrecorded-535m-impairment-charge-q1-shares-2. (113) Kang, E. G.; Wu, S.; Gupta, A.; von Mackensen, Y. L.; Siemetzki, H.; Freudenberg, J. M.; Wigger-Alberti, W.; Yamaguchi, Y. A phase I randomized controlled trial to evaluate


Page 57 of 67 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


safety and clinical effect of topically applied GSK-2981278 ointment in a psoriasis plaque test. Br J Dermatol. 2018, 178, 1427-1429. (114) GlaxoSmithKline. https://www.gsk.com/en-gb/media/press-releases/gsk-delivers-furtherprogress-in-q2-and-sets-out-new-priorities-for-the-group/. Press release, Second quarter 2017. (115) Guo, Y.; MacIsaac, K. D.; Chen, Y.; Miller, R. J.; Jain, R.; Joyce-Shaikh, B.; Ferguson, H.; Wang, I. M.; Cristescu, R.; Mudgett, J.; Engstrom, L.; Piers, K. J.; Baltus, G. A.; Barr, K.; Zhang, H.; Mehmet, H.; Hegde, L. G.; Hu, X.; Carter, L. L.; Aicher, T. D.; Glick, G.; Zaller, D.; Hawwari, A.; Correll, C. C.; Jones, D. C.; Cua, D. J. Inhibition of RORγT skews TCRα gene rearrangement and limits T cell repertoire diversity. Cell Rep. 2016, 17, 32063218. (116) Ueda, E.; Kurebayashi, S.; Sakaue, M.; Backlund, M.; Koller, B.; Jetten, A. M. High incidence of T-cell lymphomas in mice deficient in the retinoid-related orphan receptor RORγ. Cancer Res. 2002, 62, 901-909. (117) Liljevald, M.; Rehnberg, M.; Söderberg, M.; Ramnegård, M.; Börjesson, J.; Luciani, D.; Krutrök, N.; Brändén, L.; Johansson, C.; Xu, X.; Bjursell, M.; Sjögren, A. K.; Hornberg, J.; Andersson, U.; Keeling, D.; Jirholt, J. Retinoid-related orphan receptor γ (RORγ) adult induced knockout mice develop lymphoblastic lymphoma. Autoimmun Rev. 2016, 15, 10621070. (118) Okada, S.; Markle, J. G.; Deenick, E. K.; Mele, F.; Averbuch, D.; Lagos, M.; Alzahrani, M.; Al-Muhsen, S.; Halwani, R.; Ma, C. S.; Wong, N.; Soudais, C.; Henderson, L. A.; Marzouqa, H.; Shamma, J.; Gonzalez, M.; Martinez-Barricarte, R.; Okada, C.; Avery, D. T.; Latorre, D.; Deswarte, C.; Jabot-Hanin, F.; Torrado, E.; Fountain, J.; Belkadi, A.; Itan, Y.;



Boisson, B.; Migaud, M.; Arlehamn, C. S. L.; Sette, A.; Breton, S.; McCluskey, J.; Rossjohn, J.; de Villartay, J. P.; Moshous, D.; Hambleton, S.; Latour, S.; Arkwright, P. D.; Picard, C.; Lantz, O.; Engelhard, D.; Kobayashi, M.; Abel, L.; Cooper, A. M.; Notarangelo, L. D.; Boisson-Dupuis, S.; Puel, A.; Sallusto, F.; Bustamante, J.; Tangye, S. G.; Casanova, J. L. Impairment of immunity to candida and mycobacterium in humans with bi-allelic RORC mutations. Science 2015, 349, 606-613. (119) Withers, D. R.; Hepworth, M. R.; Wang, X.; Mackley, E. C.; Halford, E. E.; Dutton, E. E.; Marriott, C. L.; Brucklacher-Waldert, V.; Veldhoen, M.; Kelsen, J.; Baldassano, R. N.; Sonnenberg, G. F. Transient inhibition of ROR-γt therapeutically limits intestinal inflammation by reducing TH17 cells and preserving ILC3. Nat Med. 2016, 22, 319-323. (120) Singh, S.; Maniakis-Grivas, G.; Singh, U. K.; Asher, R. M.; Mauri, F.; Elkington, P. T.; Friedland, J. S. Interleukin-17 regulates matrix metalloproteinase activity in human pulmonary tuberculosis. J Pathol. 2018, 244, 311-322.


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Figure 1

Figure 1. Therapeutic targeting of the IL-23-Th17 axis.

Figure 2

Figure 2. Early inhibitors of RORc.



Page 60 of 67

Figure 3 Crucial for ROR t potency and LXR selectivity F3 C HO

CF3

H N

S N O S O

His479

O

H2O

Arg364

Cys320 Sulfonyl group crucial for activity

F

F3C HO

OH

F

Side chain at carbon next to nitrogen improves PXR selectivity

CF3

O N O S O

Arg367

4

OH N H

5: R = H 6: R = F

F

- Improves potency -Reduces cLogP -Reverse amide not tolerated

O N H F

N O S O

Cl

X

O

N

N H

O

F

S

O

His479 7

F Ortho halogens are important for potency

Figure 3. Sulfonamides of cyclic amines.


F3C 8: X = O 9: X = CH2

R

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Figure 4 His479 F R1

Arg367

N N

H 2O

O

N R2

O O S N

O

O S

n

Me

N N

13 (GNE-3500)

10: R 1 = H, R2 = isobutyl, n = 1 11: R 1 = F, R 2 = cyclobutyl, n = 1 12: R 1 = F, R 2 = cyclobutyl, n = 0

O

O O S N

HO O O

14 (GSK-2981278) H N O

O N S O

O O S N

N

N

N

N N N

O

O

N

O

N

NC

N

O S N O

O N

O X X

X = NH, O

O O

15 (CD-12681)

Figure 4. Acyclic sulfonamides and sultam derivatives. Figure 5

Figure 5. Crystal structure of agonist ligand 12 (orange ribbon, PDB: 4WPF) and inverse agonist ligand 10 (yellow ribbon, PDB: 4WQP).



Figure 6

Figure 6. Aryl sulfonyl compounds.


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Figure 7 His479 Glu379

Glu379

O N

O H2N

F CD3

O

N

N

O

F CD3

N

HN

30: R = F 31: R = Cl

N N

28

29

Glu379

H N

Cl O

Phe377

S

N

Me

H N

N

N

N

O N

O

H 2O

His479 N

Cl

N

N

Cl

O

33

N

32

Arg367

OCH3 O Phe377 N

CN

34 (R = CF3) 35 (R = OCH3)

O

H N

F

R

H N

Si

O

F

N

N

N O

Glu379 36 Arg364 O

H2O Gln286

OCH3 N

Phe377 F

N

Phe377

H2O

N

HN O

H N

N

N

N O

O

R

N

Cl

Leu287

Me

H N

N

O

O

CF3

N

Cl

His479

Cl

H 2O

O COOH

Arg364

Glu379

Glu379 38 37 (TAK-828F)

Figure 7. Amide/Bis-amide derivatives.


H 2O

COOH

O


Page 64 of 67

Figure 8 Gln329 Aln497

COOH O

OH

R2

R1 N

N Cl

F

F3C X= X= X= X=

N

N Cl

O

N N Cl

N

N Cl

N

O

O

O

F3C

F3C CF3

O

39: 40: 41: 42:

COOH

COOH

Phe498 N

X

HO

43

44

45

C-H, R1 = R 2 = H, MRL-871 C-F, R 1 = F, R 2 = H, MRL-299 N, R1 = F, R2 = OH, MRL-367 N, R1 = F, R2 = H, MRL-248

Figure 8. Allosteric inhibitors. Figure 9

Figure 9. Cocrystal structure of allosteric ligand 39 (MRL-871) and orthosteric ligand 1 (T0901317) with RORγt-LBD.


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Figure 10

Figure 10. Miscellaneous inhibitors (Part 1).



Figure 11

Figure 11. Miscellaneous inhibitors (Part 2).


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TABLE OF CONTENT GRAPHIC Psoriasis Respiratory disorders

Diabetes

Multiple Sclerosis RORc Inhibitors

Rheumatoid Arthritis

Psoriatic Arthritis

Ankylosing Spondylitis Crohn's disease


Combating Autoimmune Diseases With Retinoic Acid Receptor

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