Discovery of novel quinoline sulphonamide derivatives as potent, selective and orally active RORγ inverse agonists

Article abstract of DOI:10.1016/j.bmcl.2019.05.015

A high-throughput screen against Inventiva's compound library using a Gal4/RORγ-LBD luciferase reporter gene assay led to the discovery of a new series of quinoline sulphonamides as RORγ inhibitors, eventually giving rise to a lead compound having an inte

Full text of DOI:10.1016/j.bmcl.2019.05.015

Accepted Manuscript
Discovery of novel quinoline sulphonamide derivatives as potent, selective and
orally active RORγ inverse agonists
Jérôme Amaudrut, Maria A. Argiriadi, Martine Barth, Eric C. Breinlinger,
Didier Bressac, Pierre Broqua, David J. Calderwood, Mohamed Chatar, Kevin
P. Cusack, Stephen B. Gauld, Sébastien Jacquet, Rajesh V. Kamath, Michael E.
Kort, Valérie Lepais, Jean-Michel Luccarini, Philippe Masson, Christian
Montalbetti, Laurent Mounier, Dominique Potin, Olivia Poupardin, Sylvie
Rouaud, Luc Spitzer, Craig D. Wallace
PII:
S0960-894X(19)30301-4
https://doi.org/10.1016/j.bmcl.2019.05.015
BMCL 26435
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
5 March 2019
2 May 2019
7 May 2019
Please cite this article as: Amaudrut, J., Argiriadi, M.A., Barth, M., Breinlinger, E.C., Bressac, D., Broqua, P.,
Calderwood, D.J., Chatar, M., Cusack, K.P., Gauld, S.B., Jacquet, S., Kamath, R.V., Kort, M.E., Lepais, V.,
Luccarini, J-M., Masson, P., Montalbetti, C., Mounier, L., Potin, D., Poupardin, O., Rouaud, S., Spitzer, L., Wallace,
C.D., Discovery of novel quinoline sulphonamide derivatives as potent, selective and orally active RORγ inverse
agonists, Bioorganic & Medicinal Chemistry Letters (2019), doi: https://doi.org/10.1016/j.bmcl.2019.05.015
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Discovery of novel quinoline sulphonamide
derivatives as potent, selective and orally
active RORγ inverse agonists
Leave this area blank for abstract info.
Jérôme Amaudruta, Maria A. Argiriadib, Martine Bartha, Eric C. Breinlingerb, Didier Bressaca, Pierre Broquaa,
David J. Calderwoodc, Mohamed Chatara, Kevin P. Cusackb, Stephen B. Gauldd, Sébastien Jacqueta, Rajesh V.
Kamathc, Michael E. Kortd, Valérie Lepaisa, Jean-Michel Luccarinia, Philippe Massona, Christian Montalbettia,
Laurent Mouniera, Dominique Potina, *, Olivia Poupardina, Sylvie Rouauda, Luc Spitzera, Craig D. Wallacec
aInventiva, 50 rue de Dijon, 21121 Daix, France
bAbbVie, 381 Plantation Street, Worcester, MA 01605, USA
cAbbVie, 100 Research Drive, Worcester, MA 01605, USA
AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, USA

Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com
Discovery of novel quinoline sulphonamide derivatives as potent, selective and
orally active RORγ inverse agonists
Jérôme Amaudruta, Maria A. Argiriadib, Martine Bartha, Eric C. Breinlingerb, Didier Bressaca, Pierre
Broquaa, David J. Calderwoodc, Mohamed Chatara, Kevin P. Cusackb, Stephen B. Gauldd, Sébastien
Jacqueta, Rajesh V. Kamathc, Michael E. Kortd, Valérie Lepaisa, Jean-Michel Luccarinia, Philippe Massona,
Christian Montalbettia, Laurent Mouniera, Dominique Potina, , Olivia Poupardina, Sylvie Rouauda, Luc
Spitzera, Craig D. Wallacec
aInventiva, 50 rue de Dijon, 21121 Daix, France
bAbbVie, 381 Plantation Street, Worcester, MA 01605, USA
cAbbVie, 100 Research Drive, Worcester, MA 01605, USA
dAbbVie, 1 North Waukegan Road, North Chicago, IL 60064, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
A high-throughput screen against Inventiva’s compound library using a Gal4/RORγ-LBD
luciferase reporter gene assay led to the discovery of a new series of quinoline sulphonamides as
RORγ inhibitors, eventually giving rise to a lead compound having an interesting in vivo profile
after oral administration. This lead was evaluated in a target engagement model in mouse, where
it reduced IL-17 cytokine production after immune challenge. It also proved to be active in a
multiple sclerosis model (EAE) where it reduced the disease score. The synthesis, structure
activity relationship (SAR) and biological activity of these derivatives is described herein.
Keywords:
RORt inverse agonist
Th17 cells
2019 Elsevier Ltd. All rights reserved.
IL-17
Nuclear hormone receptor
SAR
———
 Corresponding author. e-mail: dominique.potin@inventivapharma.com

RORγ (Retinoic acid-related Orphan Receptor γ) is a nuclear
receptor from a family consisting of three members (together with
RORα and RORβ).1 RORα which is widely expressed, plays a role
in lipid regulation in the liver and regulates circadian rhythm in the
CNS. RORβ is mainly expressed in the cerebral cortex and the
retina where it plays a role during development. RORγ is
expressed in thymus, skeletal muscles, skin, adipose tissue and
kidney ; it has an isoform called RORγt which is identical in
sequence with the exception of a few missing amino acids on the
N-terminal side. RORγt is expressed in immune cells such as Th17
and γδTcells.2 The ligand binding domain (LBD) of the three
RORs is highly similar making the obtaining of selective
compounds quite challenging. This binding site is highly lipophilic
especially in the vicinity of Helix 10 (Fig. 1),3 the only polar part
being close to two arginine residues (Arg364 and Arg367). This
polar area has an opening to the solvent and water molecules are
found in this region in many published RORγ XRay structures.4
compound that is orally active in a mouse experimental
autoimmune encephalomyelitis (EAE) model, a preclinical model
for multiple sclerosis.
Figure 1. ROR LBD bound to 20-hydroxycholesterol in green (PDB:
3KYT) in agonist conformation, colored according to lipophilicity (from
brown: highly lipophilic to blue: hydrophilic).
During the optimization phase three different assays have been
routinely used to characterize the compounds. The first one, the
Gal4/RORγ-LBD luciferase reporter gene assay, is similar to the
one used during the HTS campaign. The compounds were then
evaluated in an IL-17a secretion inhibition assay in human Th17
cells. Finally the selectivity vs the other ROR isoforms was
evaluated in a coactivator recruitment assay using alphascreenTM
RORγt is a key player in the IL-17 pathway. It is involved in
the differentiation of naive Tcells into Th175 where both RORα
and RORγ are highly expressed. It is also involved in the synthesis
of proinflammatory cytokines such as IL-17a, IL-17f and IL-22.
Anti IL-17 antibodies such as secukinumab have shown the
interest of blocking IL-17 for treating psoriasis6 and psoriatic
arthritis.7 A small molecule RORγt inverse agonist would, in
theory, have an advantage over the antibody by blocking the
cascade upstream at two different stages, making it a good
candidate in the treatment of IL-17/Th17 mediated autoimmune
diseases.8 Such an interesting target has drawn attention from
many research groups.9
technology. As compounds were very selective for RORγ vs
RORβ (RORβ EC50 > 30µM) only the selectivity vs RORα is
indicated. This data is reported in the subsequent SAR (Structure
Activity Relationship) tables.
A high throughput screen (HTS) was run against Inventiva’s
collection (248k compounds) looking for inverse agonist activity
in a luciferase reporter gene assay using a chimeric receptor Gal4
DNA-binding domain (DBD)- human RORγ LBD transiently
transfected in COS-7 cells. T0901317 (Fig. 2) was used for
normalization as giving 100% antagonist response in all in vitro
experiments.10 Although the hit rate was quite low (0.17%),
relatively potent hits were identified including a small series of
quinoline sulphonamides exemplified by compound 1 which
displays micromolar activity (Fig. 2). Herein we report
modifications to this structure, leading to potent and selective
RORγ inverse agonists which inhibited IL-17a production in a
cellular assay. These efforts culminated in the identification of a
Figure 2. Structure of reference and hit compounds.
Our first modification of the compounds was to look at the
quinoline substitution (Table 1). Activity increased with the size
of the substituent at position 2, however with a loss of selectivity
towards RORα. Introduction of polar groups in this position -
alcohols, ether, amines - was not tolerated (data not shown).
Replacement of the imidazole in 4-position by a trifluoromethyl
group improved potency in the GAL-4 assay but came with loss in
human and mouse microsomal stability.
Table 1
SAR around quinoline substitution.

hROR EC50 a (µM)
(%eff)b
Compd.
R2
R4
IL17 inhibition EC50 c (µM)
(%eff)b
Selectivity d hClint,u e mClint,u e
(L/h/kg)
(L/h/kg)
T0901317
1
1.08 (100%)
0.93 (100%)
418
49
Me
iPr
1.36 (107%)
0.52 (113%)
0.17 (106%)
3.00 (72%)
2
2
1
16
8
2
3
nd
13
12
CF3
3.32 (77%)
8
4
5
6
Me CF3
0.25 (108%)
0.35 (105%)
0.17 (111%)
0.21 (89%)
0.21 (108%)
0.77 (97%)
32
23
9
15
18
30
83
77
98
Et
CF3
CF3
iPr
a Gal4/RORγ-LBD luciferase reporter gene assay. b Percent efficacy represents maximum inhibition (100% being the maximum
activity of T0901713). c Inhibition of IL-17 secretion in human Th17 cells. d Selectivity in the alphascreenTM assay expressed as ratio of
RORα EC50/RORγ EC50. e Human and mouse microsomal unbound clearance. All assay results are reported as the geometric mean of at
least two separate runs.
Table 2 outlines the SAR effort on the dichlorosulfonamide
moiety. Removal of the chlorine atoms in the central ring was
deleterious to the activity (compounds 4 and 7, Table 2). These
two chlorine atoms are locking the quinoline ring in a position
perpendicular to the plane of the dichlorophenyl ring. The energy
barriers of rotation around the phenyl Carom-C and benzyl C-O
bonds have both been calculated to be ~ 5 kcal.mol-1 using the
OPLS3e force field.11 Such a spatial arrangement can be seen for
example in the published structure of 2,6-dichlorobenzyl 4-
nitrophenyl ether (Fig. 3).
Switching from a secondary methylamide 4 to a primary amide
8 decreased activity and microsomal stability, but with an
improved selectivity for ROR. The carboxylic derivative 9 is
significantly less potent. The methoxy ether derivative 11 is
equivalent to compound 4 with a slightly lower potency in
inhibition of IL-17 secretion (72% vs 86%). Unsubstituted
pyrrolidine and piperidine derivatives 13 and 14 are less active.
Introduction of polar groups such as in alcohol 15 restores the
activity. From these initial SAR observations, it was hypothesized
that the quinoline part of the molecule was sitting in the lipophilic
area close to Helix H10 and that the sulphonamide moiety was
pointing in the polar area close to Arg364 and Arg367. The more
polar carboxylic acid 9 seemed not to be tolerated in this slightly
polar environment as its activity dropped significantly. This could
result from a solvation issue. Although polar groups in general
were predicted to be fitting well in the polar area close to Arg364
and Arg367, the actual prediction of activity based on docking
experiments proved to be quite challenging due to the presence of
many water molecules in this portion of the LBD and the difficulty
to accurately evaluate their contribution to the binding of the
ligand. We thus had to rely on a library approach where the
position of the polar group was explored in a systematic way using
different chain lengths and orientations. The initially found N-
methylprolinamide group remained one of the best substituent on
the sulphonamide.
Figure 3. X-Ray structure of 2,6-Dichlorobenzyl 4-nitrophenyl ether
(CSD: VAFBIN).
Table 2
SAR around phenyl linker and sulphonamide substitutions.

hROR EC50 a (µM)
(%eff)b
Compd.
R3
IL17 inhibition EC50 c (µM)
(%eff)b
Selectivity d
hClint,u e
(L/h/kg)
mClint,u e
(L/h/kg)
4
7
8
9
Cl
H
0.25 (108%)
0.21 (86%)
32
15
83
>10 (30%)
0.44 (108%)
1.39 (96%)
nd
nd
3
46
Cl
Cl
0.47 (88%)
nc (64%)
> 380
> 190
10
0.5
756
0.8
10
11
Cl
Cl
0.96 (111%)
0.16 (102%)
0.83 (93%)
0.16 (72%)
22
15
27
98
97
> 70
12
13
14
15
16
Cl
Cl
Cl
Cl
Cl
0.91 (105%)
0.81 (59%)
0.90 (77%)
0.39 (96%)
0.22 (84%)
nc (93%)
0.30 (67%)
nd
nd
10
14
14
22
19
52
58
60
65
56
> 45
> 40
> 200
> 7
nc (76%)
nd
17
Cl
0.76 (103%)
nc (90%)
> 190
26
103
a Gal4/RORγ-LBD luciferase reporter gene assay. b Percent efficacy represents maximum inhibition (100% being the maximum
activity of T0901713). c Inhibition of IL-17 secretion in human Th17 cells. d Selectivity in the alphascreenTM assay expressed as ratio of
RORα EC50/RORγ EC50. e Human and mouse microsomal unbound clearance. All assay results are reported as the geometric mean of at
least two separate runs.
Figure 4. Crystal structure of human ROR LBD bound to compound 3 (PDB: 6Q2W), with zoom on the water network in the sulphonamide region.
A co-crystal structure of ROR LBD with compound 3 was
obtained and confirmed our docking hypothesis (Fig. 4). The
imidazole moiety makes two hydrogen bonds with the backbone
NH of Gln478 and His479. The sulphonyl group is hydrogen
bound to the backbone NH of Glu379 via a water molecule. The
amide group borne by the proline is pointing towards the solvent.
There are many water molecules filling the pocket in the proximity
of Arg364 and Arg367. As expected the ligand has a conformation
where the plane of the quinoline is perpendicular to the one from
the dichlorophenyl central ring.
His479, Tyr502 and Trp317. Key interactions are a hydrogen bond
between His479 and Tyr502, and an edge to face - interaction
between Tyr502 and Trp317. Any disturbance of this spatial
arrangement is very likely to result in decreased agonist response
and a shift towards an antagonist conformation. This is the case
when compound 3 binds to the pocket. As shown in Figure 5,
His479 residue is pushed away from its agonist conformation, the
ligand also induces a kink in Helix 10 which in turn greatly
disturbs the organization of H11 and H12. The latter is no longer
resolved in the crystal structure, probably because of its high
mobility caused by the impossibility to reach its stable agonist
conformation. Interestingly, two hydrogen bonds are observed
between the ligand and the backbone nitrogen atoms of residues
Gln478 and His479. It is expected that these interactions stabilize
In its agonist conformation, the helix H12 of ROR is locked in
a position allowing the recruitment of the co-activators which are
required for the transcription to occur. The triad of essential amino
acids for the stabilization of ROR in this conformation are

the kinked conformation of helix 10 and contribute to the
antagonist character of the ligand.
increased significantly this selectivity to 133 fold in favor of
ROR. With a 2-isopropyl group, the activity was increased.
Here again the 4-pyridyl derivative 27 was quite active and
poorly selective, whereas the 4-imidazolyl derivative 29 gave
a comparable activity with a very good selectivity (>2500 x)
against ROR. This compound was chosen for further in vivo
characterization.
With the prolinamide in place, a new set of compounds was
prepared trying to modify the imidazole on the quinoline 4-
position (Table 3). The 3- and 4-pyridyl derivatives 23 and 24
were quite interesting in terms of activity but with a moderate
ROR/ROR selectivity. The 4-imidazolyl substitution of 18
Figure 5. Switch from agonist to inverse agonist conformation: ROR LBD in agonist conformation as bound to 20-hydroxycholesterol (blue gray, PDB:
3KYT) and in inverse agonist conformation when bound to compound 3 (pink, PDB : 6Q2W).
Table 3
SAR around quinoline substitution.
Compd. R2
R4
IL17 inhibition EC50 c (µM)
(%eff)b
Selectivity d
49
hClint,u e mClint,u e
hROR EC50 a (µM)
(%eff)b
1.36 (107%)
(L/h/kg)
(L/h/kg)
1
Me
3.00 (72%)
1.39 (78%)
nt
2
16
18
19
4
Me
Me
Me
Me
Me
Me
Me
Me
1.51 (104%)
>10 (100%)
0.25 (108%)
0.32 (109%)
0.88 (114%)
1.66 (106%)
0.10 (113%)
0.63 (111%)
133
5
2
7
7
55
83
nt
CF3
Ph
0.21 (89%)
0.89 (108%)
nt
32
15
nt
28
11
14
13
20
21
22
23
24
10
OBn
32
109
44
42
33
2.07 (73%)
1.01 (87%)
nc (91%)
> 240
16
81

25
26
27
28
29
iPr
iPr
iPr
iPr
iPr
0.52 (113%)
0.17 (111%)
0.22 (108%)
0.94 (109%)
0.22 (114%)
nt
13
2
8
CF3
0.77 (97%)
1.83 (104%)
>5 (117%)
0.15 (92%)
9
30
20
40
2
98
38
73
6
5
OBn
7
> 2500
a Gal4/RORγ-LBD luciferase reporter gene assay. b Percent efficacy represents maximum inhibition (100% being the maximum
activity of T0901713). c Inhibition of IL-17 secretion in human Th17 cells. d Selectivity in the alphascreenTM assay expressed as ratio of
RORα EC50/RORγ EC50. e Human and mouse microsomal unbound clearance. All assay results are reported as the geometric mean of at
least two separate runs.
Synthesis of compound 29 started with the condensation of
o-anisidine 30 with -ketoester 31 in polyphosphoric acid
(PPA) (Fig. 6). To get a reasonably good yield in this reaction,
it was essential to proceed with a two-step heating, starting with
a plateau at 110°C before increasing to 150°C.12 Chlorination
followed by demethylation yielded chloroquinolinol 33.
Protection of the phenol with a benzyl group and subsequent
conversion of the chloro to the pinacol boronate derivative 34
was realized with a quantitative yield. The imidazolyl group
was then installed through a Suzuki coupling reaction under
microwave irradiation. Debenzylation was then performed
using ammonium formate as a source of hydrogen to deliver
quinolinol 37. The southern part of the molecule 40 was
prepared using a previously reported procedure13 and was
condensed under basic conditions with quinolinol 37. Ester
hydrolysis followed by an amide coupling with methylamine
completed the synthesis of compound 29.
Figure 6. Synthesis of compound 29. a) PPA, 110°C then 150°C, 30% ; b) POCl3, PCl5, 120°C, 33% ; c) AlCl3, toluene reflux, 89% ; d) BnBr, K2CO3, DMF,
100% ; e) bis(pinacolato)diboron, Pd(OAc)2, dioxane, 110°C, 99% ; f) Pd(PPh3)4, Na2CO3, dioxane, H2O, microwave, 60% ; g) ammonium formate, Pd/C, MeOH
reflux, 96% ; h) NBS, benzoyl peroxide, CCl4 reflux, 47% ; i) (S)-Proline methyl ester HCl, Et3N, CH2Cl2, 0°C, quant. ; j) K2CO3, DMF, 49% ; k) LiOH, THF,
H2O, 99% ; l) MeNH2, EDCI HCl, HOBt, CH2Cl2, 77%.
Compound 29 was evaluated in mouse PK at 10 mg/kg po and
1 mg/kg iv (Table 4).

Table 4
PK parameters of compound 29 after administration in mouse
(iv: 1 mg/kg, po: 10 mg/kg)
PK parameter
Data
po Tmax
0.25 h
po Cmax
po AUClast
Clp,u
3324 ng/mL
3903 ng*h/mL
97 L/h/kg
1.65 L/h/kg
0.16 h
Clp
iv t1/2
Bioavailability, F
64 %
po = suspension in 1% Methylcellulose 400cp + 0.1% Poloxamer
188 ; iv = Cremophor EL 2% in 0.9% NaCl solution
Compound 29 was first evaluated in vivo in a mechanistic
model where mice were first immunized with a mixture of mouse
MOG35-55 peptide (Myelin Oligodendrocyte Glycoprotein) and
PTX (pertussis toxin). After 5 days, the test compound was
administered 45 minutes before a challenge with anti-CD3. Two
hours later, circulating cytokines were measured (Fig. 7). As
expected for a ROR inverse agonist, compound 29 had a
significant dose- dependent effect on Th17 cytokines (IL-17a, IL-
17f, and IL-22 to a lesser extent) starting from the dose of 30
mg/kg. The effect on Th1 cytokines (IFN, IL2 and TNF) and on
Th2 cytokines (IL-6 and IL-10) were non-significant (see
Supplementary Data).
Figure 7. Effect of compound 29 on anti-CD3 induced cytokines
production in mice. Compound was orally administered as a suspension in
methyl cellulose 400cp + 1% poloxamer. Global p value<0.0001, Dunnett
post test ; * p value<0.05 vs Vehicle ; ** p value<0.01 vs Vehicle ; *** p
value <0.001 vs Vehicle.

Figure 8. Effect of compound 29 in PLP-induced EAE model in mice. Compound was administered p.o. as a suspension in water in the presence of 0.1%
anti-foam (w/w).
Compound 29 was then evaluated in an EAE model in mice.
The mice were immunized with the encephalitogenic peptide of
proteolipid protein (PLP139-151), a major myelin component. In
this model, mice developed an ascending paralysis 10 to 12 days
post-immunization. The compound was administered b.i.d.
starting from the immunization. The animals were scored using a
5- point scoring system (0: normal ; 1: loss of tail tone ; 2: irregular
gait, 3: partial hind limb paralysis, 4: total hind limb paralysis, 5:
moribund). The S1P agonist fingolimod (FTY720) was used as a
positive control in this experiment. Compound 29 given orally
b.i.d. at 60 and 100 mg/kg p.o inhibited disease onset by 81 and
76%, respectively (Fig. 8).
Table 5.
Ascending dose PK of compound 29 in mice.
Dose po (mg/kg)
Tmax (h)
Cmax (ng/mL)
Cmax ratio
Oral AUClast (ng*h/mL)
Oral AUClast ratio
po t1/2 (h)
10
30
100
3
27541
8.3
269552
58
2.2
0.25
3324
1
3903
1
0.25
11754
3.5
34186
8.8
< 1
1
Compound administered as a suspension in 1%Methylcellulose
400cp + 0.1% Poloxamer
For further developing compound 29, an ascending dose PK
study was performed in mice at 10, 30 and 100 mg/kg (Table 5 and
Fig. 9). There was a dose proportional increase of Cmax with a
slower absorption at 100 mg/kg (from 0.25 h to 3 h). A more than
dose proportional increase of exposure was observed when
increasing the dose from10 mg/kg up to 100 mg/kg (giving a 58
fold increase instead of the expected 10 fold), probably due to
elimination saturation (increase of t1/2 with the dose). Slower
elimination of compound 29 could be due in part to high CYP3A4
inhibition (CYP inhibition at 1µM : 3A4 (99%), 2C9 (100%)), as
compound 29 is metabolized mostly by this cytochrome (fraction
metabolized : 3A4 (87%), 2C9 (6%)). This inhibition is very likely
linked to the presence of the imidazole. Imidazoles have indeed
been extensively reported to bind to the heme portion of the CYP.14
Introduction of bulky alkyl groups on the imidazole removed the
CYP 3A4 inhibition but at the cost of ROR activity.
In summary, we have identified
a novel series of
benzyloxyquinoline sulphonamide ROR inhibitors. They induce
the switch from an agonist to an inverse agonist structure through
the combination of a steric clash with key His479 and two
hydrogen bonds between the ligand and the protein backbone at
the beginning of helix H11 (as observed in its co-crystal structure).
Optimization of this series led to compound 29 which dose
dependently reduced secretion of pro-inflammatory cytokines IL-
17a and IL-17f in mice treated with MOG after oral administration.
Compound 29 was also active in an EAE mouse model
demonstrating the potential use of ROR inverse agonists in the
treatment of Th17-related autoimmune diseases. The good oral
exposure obtained with this compound could be mostly due to
CYP3A4 inhibition by compound 29 itself. As all attempts to get
rid of this inhibition proved to be unsuccessful, it was decided to
redesign this series of sulphonamide based ROR inverse agonists.
Acknowledgements:
We thank Fabrice Ciesielski (Novalix) for the resolution of the
crystal structure of compound 3 in ROR LBD.
References and notes
1.
(a) Jetten, A.M. Nucl. Recept. Signal. 2009, 7, e003. DOI:
10.1621/nrs.07003.
(b) Cook, D.N.; Kang, H.S.; Jetten, A.M. Nucl. Receptor Res.
2015, 2, 101185. DOI: 10.11131/2015/101185.
2.
3.
4.
5.
Sutton, C.E.; Mielke, L.A.; Mills, K.H. Eur. J. Immunol. 2012, 42,
2221. DOI: 10.1002/eji.201242569.
Jin, L.; Martynowski, D.; Zheng, S.; Wada, T.; Xie, W.; Li, Y.
Mol. Endocrinol. 2010, 24, 923. DOI: 10.1210/me.2009-0507.
See Supplementary Data for examples of ROR LBD showing
water molecules in the polar area close to arginines.
Ivanov, I.I.; McKenzie, B.S.; Zhou, L.; Tadokoro, C.E.; Lepelley,
A.; Lafaille, J.J.; Cua, D.J.; Littman, D.R. Cell, 2006, 126, 1121.
DOI: 10.1016/j.cell.2006.07.035.
Figure 9. Ascending dose PK profile of compound 29 in mice.

6.
7.
Papp, K.A.; Langley, R.G.; Sigurgeirsson, B.; Abe, M.; Baker,
D.R.; Konno, P.; Haemmerle, S.; Thurston, H.J.; Papavassilis, C.;
Richards, H.B. Br. J. Dermatol. 2013, 168, 412. DOI:
10.1111/bjd.12110.
McInnes, I.B.; Mease, P.J.; Kirkham, B.; Kavanaugh, A.; Ritchlin,
C.T.; Rahman, P.; van der Heijde, D.; Landewé, R.; Conaghan,
P.G.; Gottlieb, A.B.; Richards, H.; Pricop, L.; Ligozio, G.;
Patekar, M.; Mpofu, S. Lancet, 2015, 386, 1137. DOI:
10.1016/S0140-6736(15)61134-5.
10. 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.
Mol. Pharmacol. 2010, 77, 228. DOI: 10.1124/mol.109.060905.
11. OPLS3e, Schrödinger, Inc., New York, NY, 2013 and
Shivakumar, D.; Harder, E.; Damm, W.; Friesner, R. A.; Sherman,
W. J. Chem. Theory Comput. 2012, 8, 2553. DOI:
10.1021/ct300203w.
12. This reaction proceeds likely in two steps: formation of the
enamino ester, then cyclization. It is believed that during the first
plateau at 110°C, optimal formation of the enaminoester is
occurring and that subsequent heating to 150°C is required for the
cyclization to the quinoline ring.
8.
9.
Tabarkiewicz, J.; Pogoda, K.; Karczmarczyk, A.; Pozarowski, P.;
Giannopoulos, K. Arch. Immunol. Ther. Exp. 2015, 63, 435. DOI:
10.1007/s00005-015-0344-z.
For reviews on the subject see:
13. Dodey, P.; Bondoux, M.; Houziaux, P.; Barth, M.; Ou, K. PCT
Patent WO 97/07115.
14. Ekroos, M.; Sjögren, T. Proc. Natl. Acad. Sci. USA 2006, 103,
13682. DOI: 10.1073/pnas.0603236103.
(a) Dhar, T.G.M.; Zhao ,Q.; Markby , D.W. Ann. Rep. Med. Chem.
2013, 48, 169. DOI: 10.1016/B978-0-12-417150-3.00012-0.
(b) Bronner, S.M.; Zbieg, J.R.; Crawford, J.J. Expert Opin. Ther.
Pat. 2017, 27, 101. DOI: 10.1080/13543776.2017.1236918.
(c) Tice, C.M.; Bukhtiyarov, Y.; Zheng, Y.J.; Lala , D.; Singh,
S.B. Med. Chem. Rev. 2017, 52, 195. DOI:
10.29200/acsmedchemrev-v52.ch11.
(d) Pandya, V.B.; Kumar, S.; Sachchidanand; Sharma, R.; Desai,
R.C. J. Med. Chem. 2018, 61, 10976. DOI:
10.1021/acs.jmedchem.8b00588.
For recent papers see:
(e) Duan, J.J.W. ; Lu, Z. ; Jiang, B. ; Stachura, S. ; Weigelt, C.A. ;
Sack, J.S. ; Khan, J. ; Ruzanov, M. ; Galella, M.A. ; Wu, D.R. ;
Yarde, M. ; Shen, D.R. ; Shuster, D.J. ; Borowski, V. ; Xie, J.H. ;
Zhang, L. ; Vanteru, S. ; Gupta, A.K. ; Mathur, A. ; Zhao, Q. ;
Foster, W. ; Salter-Cid, L.M. ; Carter, P.H. ; Dhar, T.G.M. ACS
Med. Chem. Lett. 2019, 10, 367. DOI:
10.1021/acsmedchemlett.9b00010.
(f) Kotoku, M. ; Maeba, T. ; Fujioka, S. ; Yokota, M. ; Seki, N. ;
Ito, K. ; Suwa, Y. ; Ikenogami, T. ; Hirata, K. ; Hase, Y. ; Katsuda,
Y. ; Miyagawa, N. ; Arita, K. ; Asahina, K. ; Noguchi, M. ;
Nomura, A. ; Doi, S. ; Adachi, T. ; Crowe, P. ; Tao, H. ; Thacher,
S. ; Hashimoto, H. ; Suzuki, T. ; Shiozaki M. J Med Chem. 2019,
62, 2837. DOI: 10.1021/acs.jmedchem.8b01567.
(g) Tian, J. ; Sun, N. ; Yu, M. ; Gu, X. ; Xie, Q. ; Shao, L. ; Liu, J.
; Liu, L. ; Wang, Y. Eur J Med Chem. 2019, 167, 37. DOI:
10.1016/j.ejmech.2019.01.082.
(h) 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. ; Salter-Cid, L.M. ;
Barrish, J.C. ; Carter, P.H. ; Dhar, T.G.M. Bioorg Med Chem Lett.
2018, 28, 85. DOI: 10.1016/j.bmcl.2017.12.006.
(i) 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. DOI:
10.1021/acsmedchemlett.7b00476.
(j) Sasaki Y. ; Odan M. ; Yamamoto S. ; Kida S. ; Ueyama A. ;
Shimizu M. ; Haruna T. ; Watanabe A. ; Okuno T. Bioorg Med
Chem Lett. 2018, 28, 3549. DOI: 10.1016/j.bmcl.2018.09.032.
(k) Carcache D.A. ; Vulpetti A. ; Kallen J. ; Mattes H. ; Orain D. ;
Stringer R. ; Vangrevelinghe E. ; Wolf R.M. ; Kaupmann K. ; Ottl
J. ; Dawson J. ; Cooke N.G. ; Hoegenauer K. ; Billich A. ; Wagner
J. ; Guntermann C. ; Hintermann S. J Med Chem. 2018, 61, 6724.
DOI: 10.1021/acs.jmedchem.8b00529.
(l) Fukase, Y. ; Sato, A. ; Tomata, Y. ; Ochida, A. ; Kono, M. ;
Yonemori, K. ; Koga, K. ; Okui, T. ; Yamasaki, M. ; Fujitani, Y. ;
Nakagawa, H. ; Koyama, R. ; Nakayama, M. ; Skene, R. ; Sang,
B.C. ; Hoffman, I. ; Shirai J. ; Yamamoto, S. Bioorg Med Chem.
2018, 26, 721. DOI: 10.1016/j.bmc.2017.12.039.
(m) 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. Bioorg
Med Chem. 2018, 26, 483. DOI: 10.1016/j.bmc.2017.12.006.
(n) 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. Bioorg
Med Chem. 2018, 26, 470. DOI: 10.1016/j.bmc.2017.12.008.