Discovery of a potent orally bioavailable retinoic acid receptor-related orphan receptor-gamma-t (RORγt) inhibitor, S18-000003

Article abstract of DOI:10.1016/j.bmcl.2018.09.032

The retinoic acid receptor-related orphan receptor-gamma-t (RORγt) is the master transcription factor responsible for regulating the development and function of T-helper 17 (Th17) cells, which are related to the pathology of several autoimmune disorders. Therefore, ROR_γt is an attractive drug target for such Th17-mediated autoimmune diseases. A structure-activity relationship (SAR) study of lead compound 1 yielded a novel series of ROR_γt inhibitors, represented by compound 6. Detailed SAR optimization, informed by X-ray cocrystal structure analysis, led to the discovery of a potent orally bioavailable ROR_γt inhibitor 25, which inhibited IL-17 production in the skin of IL-23-treated mice by oral administration.

Full text of DOI:10.1016/j.bmcl.2018.09.032

Accepted Manuscript
Discovery of a potent orally bioavailable retinoic acid receptor-related orphan
receptor-gamma-t (RORγt) inhibitor, S18-000003
Yoshikazu Sasaki, Masahide Odan, Shiho Yamamoto, Shiro Kida, Masaya
Shimizu, Takayo Haruna, Azumi Ueyama, Ayahisa Watanabe, Takayuki Okuno
PII:
S0960-894X(18)30774-1
https://doi.org/10.1016/j.bmcl.2018.09.032
BMCL 26053
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
12 August 2018
21 September 2018
25 September 2018
Please cite this article as: Sasaki, Y., Odan, M., Yamamoto, S., Kida, S., Shimizu, M., Haruna, T., Ueyama, A.,
Watanabe, A., Okuno, T., Discovery of a potent orally bioavailable retinoic acid receptor-related orphan receptor-
gamma-t (RORγt) inhibitor, S18-000003, Bioorganic & Medicinal Chemistry Letters (2018), doi: https://doi.org/
10.1016/j.bmcl.2018.09.032
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Discovery of a potent orally bioavailable retinoic acid receptor-related orphan
receptor-gamma-t (RORt) inhibitor, S18-000003
Yoshikazu Sasakia*, Masahide Odana, Shiho Yamamotoa, Shiro Kidaa, Masaya Shimizua, Takayo
Harunaa, Azumi Ueyamaa, Ayahisa Watanabea and Takayuki Okunoa
aPharmaceutical Research Division, Shionogi & Co., Ltd., 1-1, Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan
*Corresponding author. Tel.: +81 6 6331 6727.
E-mail address: yoshikazu.sasaki@shionogi.co.jp (Y. Sasaki)
Keywords:
RORt inhibitor
Cocrystal structure with RORt LBD
Th17 cell
IL-17
Autoimmune disease
Abstract:
The retinoic acid receptor-related orphan receptor-gamma-t (RORγt) is the master transcription factor responsible for regulating the development and
function of T-helper 17 (Th17) cells, which are related to the pathology of several autoimmune disorders. Therefore, RORt is an attractive drug
target for such Th17-mediated autoimmune diseases. A structure–activity relationship (SAR) study of lead compound 1 yielded a novel series of
RORt inhibitors, represented by compound 6. Detailed SAR optimization, informed by X-ray cocrystal structure analysis, led to the discovery of a
potent orally bioavailable RORt inhibitor 25, which inhibited IL-17 production in the skin of IL-23-treated mice by oral administration.
T-helper 17 (Th17) cells, which were discovered as a unique T-helper cell lineage distinct from Th1 and Th2
cells,1 produce the interleukin 17 (IL-17) family of cytokines in response to stimulation by interleukin 23 (IL-23).
IL-23 is commonly associated with various human inflammatory and autoimmune disorders,2a including rheumatoid
arthritis,2b inflammatory bowel disease,2c multiple sclerosis2d and psoriasis.2e The retinoic acid receptor-related
orphan receptor-gamma-t (RORγt) is a nuclear receptor that has been identified as a key regulator of Th17 cell
differentiation. Therefore, RORγt may be a potential drug target for IL-23/Th17-related autoimmune diseases.
O O
S
O
MeO2C
N
H
1
h/m RORt GAL4 IC50; 0.40 / 3.1 uM
Figure 1. Structure of the SAR lead compound 1.

Several RORγt inhibitors have been reported by groups in industry and academia. There are also several reviews
summarizing recent reports of discoveries of small molecule RORγt modulators, including agonists and inverse
agonists.3 Among them, a series of RORγt inhibitors have a 4-ethylsulfonylbenzyl moiety, which GSK originally
disclosed and is now being pursued by several other companies.4,5,6,7 Our group has also explored RORγt inhibitors
based on a high-throughput screening campaign. Subsequent hit-to-lead optimization of several chemotypes led to
the identification of methyl ester derivative 1, which also possesses the ethylsulfonylbenzyl structure (Figure 1). In
this report, we describe the identification of a novel series of ,-dimethylphenylacetamide RORγt inhibitors,
which were obtained by lead optimization of 1 through a structure–activity relationship (SAR) study and guided by
a cocrystal structure analysis. These studies led to the discovery of a potent and orally bioavailable RORγt inhibitor,
S18-000003.
Table 1. SAR of amide derivatives of 1.
O
O
X
S
O
O
N
H
h/m RORt GAL4 IC50a (μM) [%eff]b
h RORt Binding IC50c (μM)
Compd.
X
1
0.40 [93] / 3.1 [77]
0.064
MeO
2
3
4
5
6
7
8
9
Me
0.37 [89] / >10 [51]
0.18 [90] / >10 [52]
0.47 [89] / 10 [55]
0.030
< 0.030
0.033
N
Me
N
N
0.43 [91] / >10 [50]
0.014 [93] / 0.47 [69]
0.014 [93] / 0.33 [76]
0.010 [93] / 0.11 [87]
0.26 [92] / 1.9 [84]
0.036
N
< 0.030
< 0.030
< 0.030
< 0.030
H
N
Me
N
N
N
a Cell-based RORγt-GAL4 promoter reporter assays.
b Percent efficacy denotes maximum inhibition activity.
c Competitive binding assays towards human RORγt.

Our initial work on the lead compound 1 focused on converting the ester moiety of 1 to various amides (Table
1). The inhibition was measured in cell-based RORγt-GAL4 promoter reporter assays, using human or mouse genes,
and also by competitive binding assays towards human RORγt (see SI for details). On the one hand, converting the
methyl ester to alkyl amides 2, 3, 4 or 5 showed no significant activity improvement. On the other hand, anilide 6
was more than 6 times more potent than the methyl ester 1 in the mouse gene assay. N-methyl anilide 7 was as
potent as 6, suggesting that the NH-proton is not important for activity. Furthermore, indoline amide 8 is also
acceptable and a more potent inhibitor than anilide 6. However, isoindoline amide 9 decreased the inhibition
activity. The binding assays demonstrated that all compounds of this chemotype inhibit RORt activity by binding
to RORt ligand-binding domain (LBD).
H11
H3
H1
His323
Glu286
His479
Leu287
H8
H7
Arg367
H5
Phe388
Phe377
H6
H2
Figure 2. Cocrystal structure of 6 in complex with human RORt LBD [PDB: 5ZA1].
His479
Phe388
Figure 3. Binding mode around the dimethylmethylene linker of 6 [PDB: 5ZA1].

Our efforts to cocrystallize anilide 6 and the human RORt LBD revealed the binding mode at a resolution of
2.52A (Figure 2, PDB: 5ZA1). The 4-ethylsulfonylbenzyl group of the ligand interacted with the protein residues
via several hydrogen bonds. The ligand sulfone moiety formed two hydrogen bonds with the side chain of Arg367
and the backbone NH of Leu287. There are two water-mediated hydrogen bonds between the carbonyl moiety of
6, the side chain of Glu286, and the backbone carbonyl of His323. Furthermore, the anilide N-H in the central part
of the compound also formed a hydrogen bond with the backbone of Phe377. One of the methyl groups of the
dimethyl methylene linker of the ligand interacted with the side chain of Phe388 via CH-π interaction (Figure 3).
The side chain of His479 formed a hydrogen bond with the carbonyl moiety of 6 and also engaged in an edge-to-
face - stacking interaction with the phenyl moiety of the compound. There was no interaction between the anilide
proton and any residues in the protein, which explains the lack of inhibitory activity difference between N-H anilide
compound 6 and N-methyl anilide 7. His479 in helix 11 is thought to play a critical role in stabilizing the interaction
of the activation function helix 2 (AF2 helix or helix 12) with coactivators by forming a hydrogen bond with Tyr502
and an edge-to-face - interaction with Phe506 on AF2 helix.8 The disruption of the His479-related interactions
could cause the disorder of secondary structure for helix 11’-12 in the RORγt LBD co-structure.9
The binding mode of the 4-ethylsulfonylbenzyl moiety of the ligand in the RORt LBD is similar to previously
reported RORt ligands that also possess this moiety.5 However, the dimethylmethylene linker made the anilide
side of the molecule form a twisted structure in the RORt LBD, which caused the terminal anilide moiety to occupy
a distinctive space in the binding pocket. In this pocket, a strong interaction between His479 and the ligand can be
formed thereby causing the orientation of His479 to differ from that observed in a previously reported RORγt
agonist ligand cocrystal structure (PDB: 3L0L);8 the previously reported cocrystal structures retain the three-
dimensional structure of H11, H11’ and H12 [PDB: 4XT9, 4NIE].5 The interactions between the anilide moiety and
His479 may be one of the critical interactions for the inhibition activity of this chemotype.
Next, we explored the SAR of the substitution pattern on the phenyl ring of the ligand again using cell-based
reporter assays (Table 2). Adding a F group at the o- or m-position increased the inhibition activity (10 and 11).
Table 2. SAR of substituents on the terminal anilide ring.
O
O
H
N
S
R
O
O
N
H
Metabolic stability
Remaining (h, r %)
8.5, 30
Compd.
R
h/m Th17 IC50c (μM)
h/m RORt GAL4 IC50a (μM) [%eff]b
6
H
o-F
m-F
p-F
o-Me
o,p-Di-F
0.014 [93] / 0.47 [69]
0.0044 [93] / 0.10 [76]
0.0098 [94] / 0.26 [84]
0.033 [93] / 0.55 [78]
0.14 [93] / 6.8 [57]
ND / 0.48
ND / 0.10
ND / 0.29
ND / 1.1
ND / ND
0.036 / 1.3
10
11
12
13
14
67, 19
2.7, 24
75, 70
24, 6
0.095 [91] / 1.8 [73]
97, 73
a Cell-based RORγt-GAL4 promoter reporter assays.
b Percent efficacy denotes maximum inhibition activity.
c Inhibitory activity towards mouse and/or human Th17 differentiation.
Especially, o-F substitution caused a four-fold increase in potency compared with that of the non-substituted anilide
6 in the mouse reporter assay. However, the introduction of a Me group at the o-position caused more than a ten-
fold loss of inhibition activity in the mouse RORt reporter assay (13). Inhibitory activity of each compound towards
mouse and/or human Th17 differentiation was also assayed and found to be similar to that of the cell-based reporter
assays. Furthermore, metabolic stability was also evaluated in both human and rat liver microsomes. Insertion of a
F group into the p-position on phenyl moiety improved the metabolic stability, however it also decreased the
inhibition activity (12, 14).
Table 3. SAR of various terminal pyridyl amide derivatives.
O
O
H
N
S
O
R
O
N
H
Solubility
Metabolic stability
Remaining (h, r %)
8.5, 30
h/m RORt GAL4 IC50a (μM) [%eff]b
Compd.
R
(pH1.2, 6.8, µM)
46.9, 26.6
>50, >50
6
Phenyl
0.014 [93] / 0.47 [69]
0.040 [93] / 1.3 [73]
0.15 [93] / 4.5 [63]
1.8 [87] / >10 [47]
15
16
17
2-pyridyl
3-pyridyl
4-pyridyl
60, 36
ND, ND
4.3, 25
ND, ND
>50, >50
a Cell-based RORγt-GAL4 promoter reporter assays.
b Percent efficacy denotes maximum inhibition activity.

For the purpose of improving the pharmacokinetic profile of 6, we next performed a SAR with a terminal pyridine
ring instead of a phenyl ring. We also evaluated the structure–solubility and structure–metabolic stability
relationships (Table 3). It was revealed that 2-substituted pyridine moiety was superior in terms of inhibition activity,
solubility and metabolic stability compared with that of 6 and all the other substitution patterns of pyridine.
Figure 4. Predicted binding mode of 15.
The SAR of the 2-substituted pyridine was explored with substitution on pyridine ring (Table 4). Prior to that, we
predicted the binding mode of 15 using MD calculation with Maestro 11.1 (Figure 4). It was estimated that the
pyridine and adjacent amide bond avoid the syn rotamer to prevent lone pair repulsion between amide carbonyl
oxygen and pyridine nitrogen.10 According to this predicted bind mode, there is space around the 4-position of the
pyridine ring, which encouraged us to insert substituents into that position in this SAR study. Insertion of a F group
Table 4. SAR of substituents on the pyridine ring.
O
O
H
N
N
S
6
O
2
3
R
O
N
4
H
Solubility
(pH1.2, 6.8, µM)
>50, > 50
>50, > 50
>50, > 50
26, 0.50
Metabolic stability
Remaining (h, r %)
60, 36
h/m RORt GAL4 IC50a (μM) [%eff]b
Compd.
R
15
18
19
20
21
22
23
H
4-F
3-F
4-CF3
6-CF3
4-Cl
4-CN
0.040 [93] / 1.3 [73]
0.031 [94] / 0.32 [86]
0.31 [92] / >10 [37]
0.025 [94] / 0.078 [94]
0.50 [90] / 5.4 [66]
69, 47
93, 80
36, 23
74, 71
40, 8.1
92, 72
1.1, 0.60
>50, 4.7
47, 25
0.0082 [95] / 0.10 [86]
0.040 [97] / 0.29 [91]
a Cell-based RORγt-GAL4 promoter reporter assays.
b Percent efficacy denotes maximum inhibition activity.
(18) increased the inhibition activity compared with that of 15. Conversely, insertion of a F group at the 3-position
(19) decreased the potency, probably because of the lack of space around the 3-position of the pyridine ring.
Likewise, 4-CF3 substituted pyridine compound 20 also had strong RORγt inhibitory activity, while 6-CF3
substituted pyridine compound 21 decreased the inhibition activity compared with that of non-substituted pyridine
15. Introduction of a Cl group to the 4-position gave analog 22, which showed good inhibition activity, but it also
showed unfavorable metabolic stability. The metabolic stability could be improved by 4-CN substitution and
moderate RORt inhibition activity was retained.11

Precise observation of the binding mode around the central aromatic ring of 6 suggested that there is some empty
space over the 3-position of aniline ring, which prompted us to insert a substituent into that position (Table 5).
Addition of a F group to the 3-position of 12 resulted in increased inhibition activity (24). Introduction of a F group
into o,p-difluoro compound 14 and 4-cyanopyridine compound 23 also increased potency (25, 26). Insertion of a F
moiety into central phenyl ring maintained good metabolic stability of each compound. Other reports also note that
introducing a Cl group to that position leads to increased potency.5a,6b Precise examination of substituents at this
position has yet to be fully optimized in our research.
Table 6. Selectivity profile of inhibitors towards other ROR family members.
Compd.
h ROR Binding IC50a (μM)
h ROR GAL4 IC50b (μM)
h LXR/ GAL4 EC50c (μM)
12
24
25
26
>10
>10
>10
>10
>10
>10
>10
>10
>30 / >30d
>30 / >30d
>30 / >30d
>30 / >30d
a Competitive binding assays towards human ROR.
b Cell-based human ROR-GAL4 promoter reporter assays.
c Cell-based human LXR/-GAL4 promoter reporter assays.
d No agonist activity on both LXR and LXR was observed up to 30 μM.
A selection of compounds were evaluated towards other members of the ROR family, as shown in Table 6, to
demonstrate selectivity for RORγt. None of these compounds bound to human ROR LBD, repressed human ROR
transcriptional activity or had human LXR/ agonist activity.
Table 7. Pharmacokinetic properties of compounds in rats.
iv,0.5 mg/ kg
po,1 mg/ kg
Tmax
Compd.
Table 5. Effect of fluoride insertion into the central aromatic ring.
AUCiv
CLtot
t1/2
Vdss
Cmax
AUCpo
BA
fu
(ng・h/mL)
986
1930
(mL/min/kg) (h)
(L/kg)
(ng/mL) (ng・h/mL)
(h)
2.5
4
(%)
(%)
3.6
3.4
5.1
R2
O
O
H
3
24
25
26
8.45
4.33
15.0
2.5
3.2
2.9
N
1.7
1.1
3.3
85.3
S
786
39.9
54.5
19.6
R1
O
185
33.3
2110
218
O
N
556
1
H
Compd.
h/m RORt
h/m Th17
Solubility
(pH1.2, 6.8, µM)
Metabolic stability
Remaining (h, r %)
h RORt
b
R1
R2
GAL4 IC50
IC50d (μM)
Binding IC50a (μM)
(μM) [%eff]c
12
24
H
F
< 0.030
< 0.030
0.033 [93] / 0.55 [78]
0.025 [95] / 0.25 [85]
0.024 / 1.1
ND / 0.42
39, 31
26, 16
75, 70
63, 77
F
F
F
25
F
< 0.030
0.029 [100] / 0.34 [85] 0.013 / 0.20
29, 25
30, 9
95, 89
82, 71
F
N
26
F
< 0.030
0.016 [95] / 0.074 [88]
ND / 0.068
CN
a Competitive binding assays towards human RORγt.
b Cell-based RORγt-GAL4 promoter reporter assays.
c Percent efficacy denotes maximum inhibition activity.
d Inhibitory activity towards mouse and/or human Th17 differentiation.
Figure 5. Effect of 25 and 26 on IL-23-induced IL-17 production in mice.
Before in vivo pharmacological studies were performed, compounds 24, 25 and 26, which all have decent RORγt
inhibition activity as well as good solubility and metabolic stability, were profiled by rat-based pharmacokinetic
studies (Table 7). Compound 26 having the largest distribution volume and the lowest in vitro metabolic stability
among these compounds showed the highest total clearance, while 25 with the lowest distribution volume and the
highest in vitro metabolic stability resulted in the lowest total clearance and the highest bioavailability.

On the basis of the in vitro efficacy against mouse Th17 differentiation and the in vivo PK profile, compounds
25 and 26 were selected for further biological evaluation. The effect of these compounds on IL-17 production in
the skin of mice injected with IL-23 is shown in Figure 5. Oral administration of both compounds inhibited IL-17
production in the skin in a dose-dependent manner. Compound 25 showed significant inhibition at a dose of more
than 30 mg/kg, and administration at a dose of 100 mg/kg resulted in 63% inhibition relative to vehicle controls.
Conversely, IL-17 production in mice dosed with 100 mg/kg of 26 was inhibited by only 38% relative to vehicle
controls, while 26 was 3-times more potent than 25 against mouse Th17 differentiation, in vitro. This is probably
due to the difference between their pharmacokinetic profiles, in vivo.12
F
F
F
F
H
O
HO
N
a
b
c, d
O
O
O
NO2
NO2
F
NO2
27
28
29
F
F
O O
S
H
N
O
O
F
N
H
25
(S18-000003)
Scheme 1. Reagents and conditions: (a) LiOH, H2O, MeOH, 50 C, (76%); (b) NBS, PPh3, DCM, 0 C then
2,4-difluoroaniline, pyridine, r.t., (95%); (c) H2, Pd/C, EtOAc, r.t.; (d) 4-(ethylsulfonyl)benzeneacetic acid,
HATU, Et3N, DMF, r.t., (2 steps 98%).
The synthesis of 25 (S18-000003) as a representative example is shown in scheme 1. Saponification of
commercially available methyl ester 27 gave carboxylic acid 28. Activation of carboxylic acid 28 with NBS and
PPh3 and simultaneous nucleophilic insertion of 2,4-difluoroaniline gave amide 29 in good yield.13 The
condensation conditions are conducive for insertion of less-nucleophilic aromatic amines. Reduction of nitro group
on 29 followed by amide formation with HATU gave the desired compound, 25 in good yield.
In summary, we have identified a novel series of ,-dimethylphenylacetamide RORγt inhibitors which have a
unique binding mode in cocrystal with RORγt LBD protein. Oral administration of these compounds, represented
by S18-00003, inhibited IL-17 production in the skin of IL-23-treated mice in a dose-dependent manner. Full details
of the SAR studies of the series and proof-of-concept studies using a psoriasis disease model animal will be reported
in due course.
Acknowledgments
We thank Kei Takiyama for his great contribution to the basic SAR study in this research, and Yuki Tachibana and Mina Yamamoto
for their helpful discussions. We are also grateful to Kazutaka Sekiguchi and Yuki Murakami for supporting the ADME experiments,
and Atsuko Nishigaki, Akira Ueda, Nobuyuki Tai and Hiroki Naruse for their great contributions to the biological studies. We are
also indebted to Azusa Nozu for her great help with MD calculation with Maestro.We thank James Murray, PhD from Edanz Group
(www.edanzediting.com/ac) for editing a draft of this manuscript.
References and notes
1. Langrish, C. L., Chen, Y., Blumenschein, W. M., Mattson, J., Basham, B., Sedgwick, J. D., McClanahan, T., Kastelein, R. A., Cua, D. J. J. Exp.
Med. 2005;201:233-240.
2. (a) Tang, C., Chen, S., Qian, H., Huang, W. Immunology 2012;135:112-24; (b) Lubberts, E. Nat. Rev. Rheumatol. 2015;11:415-29; (c) Cătană, C.,
Neagoe, I. B., Cozma, V., Magdaş, C., Tăbăran, F., Dumitraşcu, D. L. World J. Gastroenterol. 2015;21: 5823-30; (d) Jadidi-Niaragh, F., Mirshafiey,
A. Scand. J. Immunol. 2011;74:1-13; (e) Cesare, A. D., Meglio, P. D., Nestle, F. O. J. Invest. Dermatol. 2009;129:1339-50.
3. (a) Fauber, B. P., Magnuson, S. J. Med. Chem. 2014;57:5871-92; (b) Cyr, P., Bronner, S. M., Crawford, J. J. Bioorg. Med. Chem. Lett. 2016;26:4387-
93; (c) Bronner, S. M., Zbieg, J. R., Crawford, J. J. Expert Opin. Ther. Pat. 2017;27:101-12; (d) Pandya, V. B.,Kumar, S.,Sachchidanand, S.,
Sharma, R., Desai, R. C. J. Med. Chem. 2018; Article ASAP, DOI: 10.1021/acs.jmedchem.8b00588.
4. Zhang, W., Zhang, J., Fang, L., Zhou, L., Wang, S., Xiang, Z., Li, Y., Wisely, B., Zhang, G., An, G., Wang, Y., Leung, S., Zhong, Z. Mol. Pharmacol.
2012;82:583-90.

5. (a) Yang, T., Liu, Q., Cheng, Y., Cai, W., Yang, L., Wu, Q., Orband-Miller, L. A., Zhou, L., Xiang, Z., Huxdorf, M., Zhang, W., Zhang, J., Xiang,
J.-N., Leung, S., Qiu, Y., Zhong, Z., Elliott, J. D., Lin, X., Wang, Y. ACS Med. Chem. Lett. 2014;5:65-68; (b) 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, X. Bioorg. Med. Chem. 2015;23:5293-302.
6. (a) Wang, Y., Cai, W., Zhang, G., Yang, T., Liu, Q., Cheng, Y., Zhou, L., Ma, Y., Cheng, Z., Lu, S., Zhao, Y.-G., 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. Bioorg.
Med. Chem. Lett. 2014;22:692-702; (b) 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. ACS Med. Chem. Lett. 2015;6:787-92;
(c) 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. ACS Med. Chem. Lett. 2018;9:120-24; (d) Huang, Y., Yu, M., Sun, N.,
Tang, T., Yu, F., Song, X., Xie, Q., Fu, W., Shao, L., Wang, Y. Eur. J. Med. Chem. 2018;148:465.
7. (a) Gege, C. Expert Opin. Ther. Pat. 2016;26:737-44; (b) Chaudhari, S. S., Thomas, A., Khairatkar-Joshi, N., Bajpai, M. WO2013171729A2, 2013;
(c) Sharma, R., Sahu, B., Mali, S. V., Singh, D., Kumar, P. B., Dawange, M., Mistry, H. WO2015145371A1, 2015; (d) Nagamochi, M., Gotanda,
T., Goto, T., Sasaki, J., Yoshino, T., Isobe, T. JP2016128387A, 2016; (e) Zhong, X., Liu, B., Xue, Y., Li, X., Wang, F., He, W., Chen, X., Zhang,
Y., Zheng, C. CN106187838A, 2016; (f) Morphy, J. R. WO2017044410A1, 2017; (g) Brunette, S. R., Csengery, J., Hughes, R. O., Li, X., Sibley,
R., Turner, M. R., Xiong, Z. WO2017058831A1, 2017; (h) Lever, S.; Narjes, F.; Olsson, R. I.; Von Berg, S. WO2017102784A1, 2017; (i) Desai,
R., Kumar, S. S., Pandya, V., Desai, J., Raval, S. WO2018011747A1, 2018; (j) Yamamoto, S., Shirai, J., Kono, M., Shiokawa, Z., Yukawa, T.,
Imada, T., Negoro, N., Oda, T., Sasaki, S., Nara, Y.;Suzuki, S., Sato, A., Ishii, N., Shibuya, A., Nakagawa, Y., Cole, D., Gibson, T., Ivetac, A.,
Swann, S., Tyhonas, J. WO2018030550A1, 2018.
8. Jin, L., Martynowski, D., Zheng, S., Wada, T., Xie, W., Li, Y. Mol Endocrinol. 2010;24:923-29.
9. Fauber, B. P., Rene, 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. Bioorg. Med. Chem. Lett. 2014;24:3891-7.
10. Brameld, K. A., Kuhn, B., Reuter, D. C., Stahl, M. J. Chem. Inf. Model. 2008;48:1-24.
11. Jones, L. H.; Summerhill, N. W.; Swain, N. A.; Mills, J. E. Med. Chem. Commun. 2010;1:309-18.
12. The effect of RORγt inhibitors on IL-23-induced IL-17 production in mice depended on blood exposure dose as well as inhibitory activity on Th17
differentiation. Discrete PK profiles of the compounds are shown in the supporting information.
13. Froyen, P. Tetrahedron Lett. 1997;38:5359-62.
Supplementary Material
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 Highly potent RORt inhibitors discovered by a precise SAR study.
 Detailed binding mode discussion of the compound guided by X-ray cocrystal
structure analysis.
 Compounds in the series inhibited IL-17 production in the skin of IL-23-treated
mice by oral administration.