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

Article abstract of DOI:10.1016/j.bmcl.2017.12.006

We disclose the optimization of a high throughput screening hit to yield benzothiazine and tetrahydroquinoline sulfonamides as potent RORγt inverse agonists. However, a majority of these compounds showed potent activity against pregnane X receptor (PXR) and modest activity against liver X receptor α (LXRα). Structure-based drug design (SBDD) led to the identification of benzothiazine and tetrahydroquinoline sulfonamide analogs which completely dialed out LXRα activity and were less potent at PXR. Pharmacodynamic (PD) data for compound 35 in an IL-23 induced IL-17 mouse model is discussed along with the implications of a high Y_max in the PXR assay for long term preclinical pharmacokinetic (PK) studies.

Full text of DOI:10.1016/j.bmcl.2017.12.006

Accepted Manuscript
Identification of Bicyclic Hexafluoroisopropyl Alcohol Sulfonamides as Reti-
noic Acid Receptor-Related Orphan Receptor Gamma (RORγ/RORc) Inverse
Agonists. Employing Structure-Based Drug Design to Improve Pregnane X Re-
ceptor (PXR) Selectivity
Hua Gong, David S. Weinstein, Zhonghui Lu, James J.-W. Duan, Sylwia
Stachura, Lauren Haque, Ananta Karmakar, Hemalatha Hemagiri, Dhanya
Kumar Raut, Arun Kumar Gupta, Javed Khan, Dan Camac, John S. Sack,
Andrew Pudzianowski, Dauh-Rurng Wu, Melissa Yarde, Ding-Ren Shen, Virna
Borowski, Jenny H. Xie, Huadong Sun, Celia D'Arienzo, Marta Dabros, Michael
A. Galella, Faye Wang, Carolyn A. Weigelt, Qihong Zhao, William Foster, John
E. Somerville, Luisa M. Salter-Cid, Joel C. Barrish, Percy H. Carter, T.G. Murali
Dhar
PII:
S0960-894X(17)31166-6
https://doi.org/10.1016/j.bmcl.2017.12.006
BMCL 25462
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
4 October 2017
18 November 2017
4 December 2017
Please cite this article as: Gong, H., Weinstein, D.S., Lu, Z., J.-W. Duan, J., Stachura, S., Haque, L., Karmakar, A.,
Hemagiri, H., Kumar Raut, D., Kumar Gupta, A., 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., 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, Bioorganic & Medicinal Chemistry Letters (2017), doi: https://doi.org/
10.1016/j.bmcl.2017.12.006
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Bioorganic & Medicinal Chemistry Letters
Identification of Bicyclic Hexafluoroisopropyl Alcohol Sulfonamides as Retinoic
Acid Receptor-Related Orphan Receptor Gamma (ROR/RORc) Inverse
Agonists. Employing Structure-Based Drug Design to Improve Pregnane X
Receptor (PXR) Selectivity
Hua Gong,a David S. Weinstein,a Zhonghui Lu,a James J.-W. Duan,a Sylwia Stachura,a Lauren Haque,a
Ananta Karmakar,b Hemalatha Hemagiri,b Dhanya Kumar Raut,b Arun Kumar Gupta,b Javed Khan,a Dan
Camac,a John S. Sack,a Andrew Pudzianowski,a Dauh-Rurng Wu,a Melissa Yarde,a Ding-Ren Shen,a Virna
Borowski,a Jenny H. Xie,a Huadong Sun,a Celia D’Arienzo,a Marta Dabros,a Michael A. Galella,a Faye
Wang,a Carolyn A. Weigelt,a Qihong Zhao,a William Foster,a John E. Somerville,a Luisa M. Salter-Cid,a
Joel C. Barrish,a Percy H. Cartera and T. G. Murali Dhar*a
a Bristol-Myers Squibb, Research and Development, Princeton, New Jersey 08543-4000, United States. b Bristol-Myers Squibb-Biocon Research Center,
Bangalore, India.
* Corresponding author: murali.dhar@bms.com
Article history:
Received
Revised
Accepted
Available online
We disclose the optimization of a high throughput screening hit to yield benzothiazine and
tetrahydroquinoline sulfonamides as potent RORt inverse agonists. However, a majority of
these compounds showed potent activity against pregnane X receptor (PXR) and modest activity
against liver X receptor  (LXR). Structure-based drug design (SBDD) led to the
identification of benzothiazine and tetrahydroquinoline sulfonamide analogs which completely
dialed out LXR activity and were less potent at PXR. Pharmacodynamic (PD) data for
compound 35 in an IL-23 induced IL-17 mouse model is discussed along with the implications
of a high Ymax in the PXR assay for long term preclinical pharmacokinetic (PK) studies.
Keywords: ROR, retinoic acid-related orphan
receptor; PXR, pregnane X receptor; LXR, liver X
receptor; IBD, inflammatory bowel disease; RA,
rheumatoid arthritis, MS, multiple sclerosis.
2017 Elsevier Ltd. All rights reserved.
The retinoic acid-related orphan receptors belong to the NR1F
subfamily of nuclear hormone receptors. All three members –
ROR (NR1F1), ROR (NR1F2), and ROR (NR1F3) play
important roles in organ development, immunity, metabolic
regulation, neural function, and circadian rhythms.1 RORt and
ROR (RORc in human) are two splice variants that are identical
apart from an N-terminal extension of 24 amino acids present
only in RORROR is highly expressed in the thymus in
addition to kidney, liver, pancreas, muscle, and adipose, whereas
the expression of RORt is restricted to lymphoid cells. ROR
regulates the expression of genes that control metabolism in
skeletal muscle and fat and that regulate circadian rhythms in
non-immune cells. The normal differentiation and/or function of
specialized lymphocytes including IL-17 producing T helper
(Th17) cells, innate lymphoid cells (ILC),  cells and the
development of lymph nodes is dependent on RORt.
Importantly, RORt regulates the expression of pro-inflammatory
cytokines such as IL-17A,2 IL-17F, IL-22 and GM-CSF that are
implicated in several inflammatory and autoimmune diseases
such as psoriasis, inflammatory bowel disease (IBD), rheumatoid
arthritis (RA), and multiple sclerosis (MS).3
Findings from numerous studies with RORt-deficient mice
suggest that RORt is a critical component in the pathogenesis of
a range of immune and inflammatory diseases, including
psoriasis, IBD, MS, graft versus host disease (GvHD), nephritis,
asthma and cancer.4 Several small molecule inverse agonists of
RORt, have shown robust efficacy in preclinical models of
psoriasis,5 IBD,6 RA5c,6a,7,8a and MS.8 In these preclinical studies,
reduced disease severity is accompanied by a decrease in Th17-
related cytokines.
Taken together, both genetic and
pharmacologic evidence support the potential for broad clinical
utility of RORt inverse agonists for the treatment of a variety of
immune-related disorders.3,9,10 It is therefore not surprising that a
few compounds are already in clinical development, the most
advanced being (S)-N-((5-(ethylsulfonyl)pyridin-2-yl)methyl)-7-
isopropyl-6-(((1r,4S)-4-(trifluoromethyl)cyclohexyl)methyl)-6,7-
dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide
(VTP-
43742).11,12
Herein we report the structure-activity relationships (SAR) and
SAR-based optimization of a HTS hit to yield potent and
selective inverse agonists of RORt. We used reporter assays to

line. eracemic. ND = not determined
characterize the in vitro biological activities of RORt ligands
including both potency and selectivity. A Jurkat cell based Gal4
reporter assay was used to measure RORt-dependent
transcriptional luciferase activity driven by the native IL-17
promoter (see supplementary material section). Functional LXR
/ isoform activity was assessed using LXRα and LXRβ
transactivation assays in CV-1 cells.13 Functional PXR activity
was assessed using a transactivation assay in HepG2 cells.14 N-
(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)-N-
(2,2,2-trifluoroethyl)benzenesulfonamide (T0901317)15 was
employed as the positive control for the RORtinverse agonist
assay.
Before embarking on further SAR work around the cores shown
in Table 1, we decided to briefly explore the SAR around the 4-
fluorophenylsulfone moiety of 1 to determine the optimal
substitution pattern required for potency in this region of the
molecule (Table 2).
Substituting the sulfone moiety of compound 1 with a carbonyl
group leads to loss of activity at RORt (compound 8) suggesting
that the tetrahedral nature of the sulfone may be responsible for
projecting the 4-fluorophenyl group for optimal interactions with
the ligand binding domain (LBD) of RORt (vide infra). It is
interesting to note that the 2-fluoro and 3-fluoro substitution
patterns lead to significant loss in potency compared to the 4-
fluoro analog (compare 11 and 12 with 1). The loss in potency
with the 2-fluoro analog 11 may be attributed to the distortion in
orientation of the phenyl group due to repulsive interactions of
the fluoro moiety with the sulfone oxygens (vide infra).
However, the loss in potency with the 3-fluoro analog 12 is not
A HTS campaign of the Bristol-Myers Squibb (BMS) compound
deck identified compound 1 as a potential lead with an EC50 of
165 nM in the Gal4 reporter assay for RORt (Table 1). In
addition, compound 1 was significantly less potent against ROR
and ROR in cellular assays (EC50 > 20 M) and had no activity
in the agonist mode for ROR, ROR and RORt at the
concentrations tested (EC50 > 40 M). The functional selectivity
of compound 1 for ROR/, in both the agonist and the inverse
agonist mode, may be due to the differential recruitment of co-
activators/co-repressors for RORt vs. that for ROR/.
However, compound 1 showed significant activity against PXR,
LXR and LXR in the agonist mode (Table 1). We envisioned
that the PXR and LXR/ activities can potentially be minimized
while optimizing the potency of compound 1 for RORt. Table 1
outlines the SAR of the core modifications and its impact on
RORt activity and selectivity for PXR and LXR/. It is clear
from the SAR shown in Table 1 that changes to the core did not
significantly alter the potency of the compounds for RORt nor
improve the selectivity vs. PXR and LXR/. The SAR data
also indicates that the compounds were more potent at PXR than
at RORt or LXR
obvious.
The 4-chlorophenyl and chloropyridyl analogs
(compounds 13 and 16 respectively), were equipotent to 1. In
contrast to the parent phenyl analog 10 which had similar
potency to the 4-fluoro analog 1, the pyridyl analog 15 was
inactive in the RORt reporter assay, probably due to the
hydrophobic nature of the pocket in this region of the LBD (vide
infra). Although, the desfluoro, 4-chloro and the chloropyridyl
analogs (10, 13 and 16 respectively) were similar in potency to 1,
they did not offer any advantage in terms of reduced potency at
LXR/ and PXR (data not shown).
Table 2. SAR of benzothiazine sulfonamides
Table 1. Core modification SAR
R1
R2
R3
RORt EC50
nMa,b
Y
Z
1
SO2
C=O
CH2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
CH
CH
CH
CH
CH
CH
CH
CH
N
F
F
H
H
H
H
H
F
H
H
H
H
F
165 ± 40
>10000
8
PXR
LXR
LXR
RORt
EC50 nMa,b
X
S
EC50 nM
EC50 nM
EC50 nM
9
F
>10000
(% max.)c (% max.)d (% max.)d
10
11
12
13
14
15
16
H
230 ± 80
1260b
T0901
317
359 ± 15
(~90)a
198 ± 19
(~100)a
333 ± 48
8 (84)
H
H
H
H
H
H
H
2040 ± 1570
165 ± 80
530 ± 175
>10000
190 ± 34
(80)a
185 ± 15
(100)a
1
165 ± 40 20 (100)
Cl
OMe
H
H
H
H
H
2
3
4
O
203 ± 9
600c
ND
ND
265 (78)c
310 (64)c
385 (47)c
340 (86)c
445 (64)c
455 (75)c
NH
170b
NMe
170 ± 34 18 (100)
280 ± 135 25 (100)
N
Cl
aValues are means of two or more experiments performed in
triplicate. bValue from a single experiment performed in duplicate.
163 ± 74
(70)a
223 ± 75
(99)a
5
CH2
6
7
CHMee 195 ± 63 16 (100)
C(Me)2 36 (100)
815c
70 (60)c
130 (70)c
550 (80)c
Since X-ray co-crystal structures with the LBD’s of RORt
and/or PXR were not available at this point in the program, we
decided to conduct SAR empirically at the 2-position of
compound 1 in order to improve the potency of compounds for
RORt while reducing the LXR/ and PXR activity. Although
various groups were considered, we decided to pursue the acetic
290 (39)c
aValues are means of two or more experiments performed in
triplicate. bRORt reporter assay was performed using a Jurkat
cell line. cvalue from a single experiment performed in duplicate.
dLXR assays (agonist mode) were performed using a CV-1 cell

acid analog 18, since it was easily accessible and the acid moiety
synthesized and evaluated for potency vs. RORt. Table 3
enabled us to quickly evaluate SAR. A number of analogs were
summarizes data for a representative set of compounds.
Table 3. SAR of 2-substituted benzothiazine sulfonamides
RORt
PXR
LXR
LXR
EC50 nMa,b
165 ± 40
93 ± 15
2780c
EC50 nM (% max.)c
20 (100)
55 (100)
ND
EC50 nM (% max.)d
EC50 nM (% max.)d
X
1
H
190 ± 34 (80)a
250 ± 90 (75)a
>7500c
185 ± 15 (100)a
370 ± 28 (86)
>7500c
17
18
19
20
-CH2CO2Me
-CH2CO2H
-CH2CONH2
-CH2CONHMe
240c
190 (100)
ND
970 (50)c
2820 (36)c
225c
2403 ± 1340 (48)a
2470 ± 40 (30)a
21
22
84c
58c
254 (100)
380 (100)
342 ± 54 (23)a
2900 (15)c
980 ± 0.27 (40)
2450 ± 45 (20)c
23
28c
250 (100)
2070 ± 5 (27)
3120±120 (100)
24
25
114c
31 ± 12
12 ± 7
ND
1300 (30)c
>7500c
>7500
>7500
175 (90)
144 (100)
2770 ± 600 (39)
2820 ± 1275 (40)
25a†
25b
26
1640c
80c
228 (82)
3280 (34)c
374 (74)c
>7500
520 (100)
1040 (95)c
*All compounds shown in the table are racemic except for 25a and 25b. aValues are means of two or more experiments performed in triplicate. bRORt reporter
assay was performed using a Jurkat cell line. cValue from a single experiment performed in duplicate. dLXR assays (agonist mode) were performed using a CV-1
cell line. †Absolute stereochemistry established by single crystal X-ray (CCDC # 1586092).
It is clear from the data outlined in Table 3, that incorporating a
side chain at the 2-position of the benzothiazine scaffold, in
general, leads to significant improvements in potency for RORt
and selectivity vs. LXR, particularly LXR. Unfortunately, all
compounds were potent agonists of PXR. Resolution of
enantiomers of compound 25 (25a and 25b) confirmed that the
more potent isomer at RORt was also a potent full agonist of
PXR (25a). That the lack of selectivity for PXR was not unique
to the benzothiazine chemotype was confirmed by the fact that
the tetrahydroquinoline chemotype displayed a similar profile
(Figure 1).
Figure 1. RORt and PXR activity of 27 and 28 in reporter assays. Absolute
stereochemistry of peaks 1 and 2 not determined..
In order to understand the structural basis for the lack of
selectivity of this series of compounds for PXR and provide
direction to achieve selectivity, we obtained the X-ray co-crystal
structures of 2-substituted benzothiazine 25a with the LBD’s of
both RORt and PXR (Figure 2).

hydrophobic pocket formed by the side chains of Phe288,
Trp299, Tyr306, Leu209 and Val211 and is sandwiched between
Trp299 in parallel pi stacking interaction with Phe288 and
Tyr306. As in the RORt structure, the hexafluoroisopropyl
group is lodged in a pocket rich in hydrophobic residues that
includes Phe420, Met425, Leu240 and Leu411. However, unlike
the binding orientation of compound 25a in RORt where the
hydroxypropyl acetamide -OH is involved in a water-mediated
hydrogen bond with the side chain of Arg367 and backbone
carbonyl of Arg364, the hydroxypropyl acetamide moiety is
projected into an open pocket in PXR and is involved in only
weak hydrophobic interactions (~3.8 Å range) with residues in
loops near Pro227 and Ile236.
Figure 2. X-ray co-crystal structures of compound 25a with the LBD of
RORt (2A, PDB ID: 6BN6) and PXR (2B, PDB ID: 6BNS)
The X-ray co-crystal structure of 25a bound to RORt was
resolved at 2.40 Å, revealing a number of polar interactions and
van der Waals contacts between the ligand and the RORt
binding pocket and the absence of electron density for helix 12.
The destabilization of helix 12 provides further evidence for the
inverse agonist nature of the interaction of compound 25a with
the LBD of RORt. The hexafluoroisopropyl alcohol forms a
hydrogen bond with the side chain of His479,15 while one of the
sulfone oxygens forms a hydrogen bond with the side chain of
Cys320. In addition, the hydroxyl group of hydroxypropyl
acetamide moiety forms water-mediated hydrogen bonds to the
side chain of Arg367 and the backbone carbonyl of Arg364, as
well as an intramolecular hydrogen bond to the acetamide
carbonyl. The 4-fluorophenyl sulfonamide group occupies a
hydrophobic pocket formed by the side chains of Met365,
Val376, Phe378, Phe388, Ile400 and Phe401 and forms partial
parallel pi stacking interactions with Phe388 (~3.6 Å). Phe388
engages neighboring Phe378 in an edge-to-face pi stacking
interaction. The hexafluoroisopropyl group occupies a pocket
rich in hydrophobic residues that includes Trp317, Met358,
Leu396, Ile397, Ile400 and Leu483. The tetrahedral sulfone
group projects the 4-fluorophenyl moiety in a parallel plane to
the rest of the ligand, allowing for favorable hydrophobic
interactions as discussed above. This orientation cannot be
achieved by the amide analog 8, which is consistent with its
lower RORt potency.
The improved potency of compound 25a for RORt can be
rationalized by the water-mediated hydrogen bond between the
hydroxyl group of hydroxypropyl acetamide moiety with the side
chain of Arg367, backbone carbonyl of Arg364. A similar kind
of the H-bond interaction (with or without water mediation) may
explain the improved potency for RORt, seen for other
compounds in Table 3, with polar acetamide side chains
compared to compound 1. However, it was clear from the X-ray
co-crystal structures, that compound 25a was engaging the same
polar and hydrophobic interactions with the LBD’s of RORt and
PXR: the hydroxyl group of the hexafluoroisopropyl alcohol
forms hydrogen bonds with His479 or His407; the 4-
fluorophenyl group is lodged in a very hydrophobic pocket; and
the hexafluoroisopropyl moiety is lodged in a pocket rich in
hydrophobic residues in both RORt and PXR. This issue was
further exaggerated by the fact that the acetamide side chain at
the 2-position of the ligand was projecting into an open pocket in
PXR, suggesting that modifications in this region of the ligand
would be tolerated in PXR, which is consistent with the SAR
described above (Table 3).
We also noted that the 4-fluorophenylsulfonyl moiety of
compound 25a assumes a pseudoaxial orientation in the RORt
structure and engages in a pi stacking interaction with the phenyl
group anchoring the hexafluoroisopropyl alcohol moiety (vide
supra). In the PXR structure the 4-fluorophenylsulfonyl moiety
adopts a pseudoequatorial orientation, which is similar to what is
observed in the single crystal X-ray of compound 25a (CCDC #
1586092).
The X-ray co-crystal structure of 25a bound to PXR was resolved
at 2.56 Å. Similar to the structure of 25a with the LBD of
RORt, both polar interactions and a number of van der Waals
contacts are observed between the ligand and the binding pocket
of PXR. However, unlike the RORt structure, there is clear
presence of electron density for helix 12 in the PXR structure for
compound 25a. The stabilization of helix 12 provides further
evidence for the agonist nature of the interaction of compound
25a with the LBD of PXR. The hexafluoroisopropyl alcohol
moiety forms a hydrogen bond with the side chain of His407
(2.47 Å) and a water-mediated hydrogen bond with the side chain
of Ser247. The acetamide NH forms hydrogen bonding
interactions with the backbone carbonyls of Leu206 and Leu209.
Closer examination of the X-ray co-crystal structure of 25a with
the LBD of PXR suggested that moving the side chain from
position 2 of the benzothiazine scaffold to position 3 would
create a steric clash with the 1 sheet in PXR, potentially
improving selectivity while maintaining potency for RORt. To
test this hypothesis, we synthesized compounds in both the
benzothiazine and tetrahydroquinoline series. Table 4 outlines
the in vitro data for this set of compounds.
The 4-fluorophenyl sulfone moiety of 25a occupies
a

Table 4. SAR of 3-substituted benzothiazines and 2-substituted tetrahydroquinolines
PXR
LXR
EC50 nM (%
max.)d
LXR
EC50 nM (%
max.)d
RORt
HLM/MLM
R
X
S
S
EC50 nMa,b
Stability (%)e
EC50 nM (%
max.)c
25
29
31 ± 12
175 (90)
2770 ± 600 (39)
792 (100)c
>7500
64, 55
11, 2
97c
1510 (83)
>7500c
30*
31*
S
S
32c
1100 (90)
1350 (70)
>7500
>7500
3710c
5, 2
2, 1
7380c
315 (93)c
32
CH2
47c
2000 (80)
1030 (83)c
>7500c
38, 15
33†
34
CH2
CH2
CH2
15 ± 2
7500 ± 1250
39 ± 18
1830 (91)
2860 (76)
2000 (100)
>7500
320 (78)c
>7500
>7500
>7500c
>7500
59, 25
30, 0.7
56, 62
35
b
aValues are means of two or more experiments performed in triplicate. RORt reporter assay was performed using a Jurkat cell line. cValue from a
single experiment performed in duplicate. dLXR assays (agonist mode) were performed using a CV-1 cell line. eMetabolic stability in human and
*
mouse liver microsomes (HLM and MLM). Values are percentage remaining after 10 min. of incubation. Absolute stereochemistry not established.
†Absolute stereochemistry established by single crystal X-ray (CCDC # 1586093)
It is clear from the data listed in Table 4 that moving the side chain to the 3-position of the benzothiazine or the 2-position of the
tetrahydroquinoline scaffold decreases the potency of these compounds for PXR by an order of magnitude (although the Ymax
remains high), consistent with our hypothesis. Other important SAR points of note are as follows: (a) on resolution of racemic
mixtures (29 and 32), there is an approximately three fold improvement in potency for RORt (compare 29 with 30 and 32 with 33),
(b) LXR activity is eliminated in the more active RORt enantiomer (compounds 30 and 33) – all of the LXR activity resides in
the less potent RORt enantiomer (compounds 31 and 34). In order to understand the stereochemical preference for LXR activity
with compounds 31 and 34, we docked compound 34 in hLXR (PDB ID: 5HJS,16 Figure 3).

Figure 3. Model of compound 34 docked in hLXR (PDB ID: 5HJS)16
The binding model suggests the hexafluoroisopropyl alcohol forms a hydrogen bond with the side chain of His257 and the 4-
fluorophenyl sulfonamide group occupies the hydrophobic pocket formed by the side chains of Ile149, Phe162, Leu167, Phe171,
Phe175 and Phe176. One of the sulfonamide oxygens forms a hydrogen bond with the side chain of Thr138 and an intra-molecular
hydrogen bond with the acetamide NH. The acetamide moiety extends towards the polar region of the LXR LBD, allowing the
alcohol to form a hydrogen bond with the side chain of Ser100. In contrast to compound 34, we were unable to dock compounds 30
and 33 in this model. We hypothesize that the “S” orientation of the side chain in compounds 30 and 33 cannot be accommodated
without an accompanying steric clash with helix 5 in the LBD of hLXR.
Bioisosteric replacements of the amide (urea, reverse amides, sulfonamides and heterocycles) did not lead significant improvements
in RORt potency and/or selectivity vs. PXR (data not shown). It is of interest to note that moving the side chain from the 2-postion
of the benzothiazine scaffold to the 3-position significantly decreases the metabolic stability in the in vitro human and mouse liver
microsomal assay (Table 4, compare 25 with 29). Although compound 33 showed a favorable profile in terms of potency for
RORt and selectivity against LXR/ and PXR, the in vitro metabolic stability in the liver microsomal assay was less than
desirable for advancement into in vivo pharmacodynamic (PD) models. Further SAR studies led to the identification of compound
35, which had good in vitro liver microsomal stability and was advanced to a PD model.
To assess the ability of compound 35 to inhibit RORt-dependent responses in vivo, a short pharmacodynamic model was developed
that relied on IL-2 and IL-23 stimulation. Naive mice were challenged three times with IL-2 and IL-23 (at 0, 7, and 23 hours) after
IL-2 alone priming (-24 hour). Serum IL-17 was analyzed 7 hour after last IL-2/IL-23 administration. Oral dosing of compound 35
under these conditions significantly blocked the IL-17 response in a dose-dependent manner and achieved 74% inhibition at 25
mg/kg and 98% inhibition at 100 mg/kg doses, respectively (Figure 4). These data demonstrate that systemic administration of
RORt inverse agonist 35 limits IL-17 response in vivo.
Figure 4. In vivo activity of compound 35 in the IL-2/IL-23 induced IL-17 PK-PD model. # Terminal exposures from study.
Encouraged by the favorable results from the PD study, the next step was to test compound 35 in chronic mouse models of
autoimmune disorders. Before embarking on testing the compound in preclinical in vivo models, we decided to do a five day PK
study. Although the potency of compound 35 was significantly right shifted in the PXR assay (vide supra), the high Ymax suggested
that the compound can potentially act as a full agonist of PXR at concentrations above 2 M. Since activity in the PXR assay
suggests the potential to induce human Cyp3A4, we wanted to know if Cyp3a11 (mouse equivalent of Cyp3A4) is induced in an in

vitro mouse hepatocyte assay. In the event, when compound 35 was tested in the mouse hepatocyte assay, Cyp3a11 was
upregulated 21-, 47- and 40-fold at concentrations of 1, 3 and 10 M, respectively, when compared to DMSO control. Although we
did not conduct reaction phenotyping studies to understand the Cyp enzyme responsible for the metabolism of compound 35, the
induction of Cyp3a11 in in vitro studies suggested the potential for auto-induction leading to decrease in exposures upon repeat
dosing. A mouse PK study was conducted at oral doses of 30 mg/kg and 100 mg/kg of compound 35 twice daily for five days.
Exposures at day 1 and day 5 were recorded and the data are summarized in Tables 5A and 5B.
Table 5A#
Compound 35 concentration at 30 mg/kg, PO, BID* (nM)
Fold
decrease
Day 1
Day 5
Time (h)
1
Mean
3488
134
5
SD
782
35
-
Mean
555
21
SD
175
19
-
6.3
6.5
1.0
7.5
23.5
5
Table 5B#
Compound 35 concentration at 100 mg/kg, PO, BID* (nM)
Day 1 Day 5
Mean
Time (h)
1
SD
1916
1250
9
Mean
2834
61
SD
1239
37
13895
2460
19
4.9
40
-
7.5
23.5
-
-
#
PK protocol: mouse PK studies were conducted in male Balb/c mice. *vehicle for PK study: 55% PEG300/25%Proplylene
glycol/10%TPGS/10%water.
Comparing day 1 and day 5 exposures, it is clear from the data in Tables 5A/5B that there is ~5-6 fold drop in exposure at 1 h and
~7-40 fold drop in exposure at 7.5 h at both the 30 mg/kg and 100 mg/kg doses. At the end of the study, liver tissue samples were
collected and evaluated for Cyp3a11 mRNA levels. Consistent with the in vitro data, a dose dependent increase in Cyp3a11 mRNA
levels were observed (~3.5 and 5.5 fold increase over dosing vehicle group at 30 mg/kg and 100 mg/kg respectively). Although one
cannot rule out the possibility of alteration of other clearance mechanisms causing the reduced exposure on chronic dosing, the
strong in vitro-in vivo correlation suggests that increased Cyp3a11 expression may be a significant factor contributing to the
reduction in exposure due to auto-induction by compound 35. The loss in exposure in the five-day PK study limited our ability to
test compound 35 in chronic preclinical models of autoimmune disorders.
Synthetic approaches to compounds in Tables 1-4 and Figure 1 are outlined in Schemes 1-7. The hexafluoroisopropyl alcohol
moiety present in all the final compounds was introduced by alkylating an aniline substrate with hexafluoroacetone hydrate at high
temperature. The key steps in the preparation of compounds 27 and 28 were a Heck-type palladium mediated reaction of 3-
bromoquinoline (44) with a silyl enol ether, followed by selective hydrogenation of the quinoline ring using PtO2. The key step in
the preparation of compound 35 is the Horner–Wadsworth–Emmons reaction of the aminal 52 with triethyl phosphonoacetate to
form an acrylate, which undergoes an intramolecular Michael reaction via a favorable six exo-trig process to provide the
tetrahydroquinoline derivative 53 following Boc deprotection.17
Scheme 1 Conditions: (a) (1) hexafluoropropan-2-one, microwave, 160 oC, 10 min.; (2) silica gel chromatography to separate regioisomers, 43%; (b)
RSO2Cl, pyridine, DCM or RCOCl, DMAP, DCM or RCH2Br, NaH, DMSO.

o
Scheme 2 Conditions: (a) methyl 2-aminoacetate hydrochloride, Et3N, DMF, 80 C, 64%; (b) H2, Pd/C, MeOH, 40 psi, RT, 97%; (c) LAH, RT, 12 h, 64%;
o
(d) hexafluoropropan-2-one, PTSA, microwave, 45 min., 80 C, prep. HPLC to separate regioisomers, 41%; (e) 4-fluorobenzenesulfonyl chloride, pyridine,
DCM, Prep. HPLC to separate regioisomers, 4%.
Scheme 3 Conditions: (a) BH3, THF, 78%; (b) hexafluoropropan-2-one, PTSA, 100 oC, 12 h, 46%; (c) 4-fluorobenzenesulfonyl chloride, pyridine, DCM,
RT, 12 h, 32%; (d) LiOH, THF, H2O, RT, 1 h, 90%; (e) RR1NH, BOP, DMF, DIPEA.
Scheme 4 Conditions: (a) DPPA, Et3N, 2-(trimethylsilyl)ethan-1-ol, 100 oC, 30 min., 65%; (b) TBAF, THF, RT, 2 h, 90%; (c) BOP, DMF, DIPEA, RT, 1 h,
50%.
o
Scheme 5 Conditions: (a) tert-butyl((1-methoxyvinyl)oxy)dimethylsilane, Pd(Tol3P)2Cl2, KOAc, toluene, 110 C, 30 h, 72%; (b) PtO2, H2, MeOH, 70%; (c)
o
hexafluoropropan-2-one, PTSA, microwave, 40 min., 70 C, 61%; (d) 4-fluorobenzenesulfonyl chloride, pyridine, DCM, 24 h, 58%; (e) LiOH, THF, H2O,
RT, 3 h, 86%; (f) HATU, DIPEA, DMF, RT, 3 h, Chiralcel OD-H column.
Scheme 6 Conditions: (a) [(CH3)3COCO]2O, DMAP, CH3CN, RT, 15 h, 100%; (b) LiEt3BH, THF, -78 oC, 30 min.; (c) triethyl phosphonoacetate, NaH,
o
THF, 79% (over two steps); (d) TFA, DCM; (e) hexafluoropropan-2-one, PTSA, 120 C, 12 h, 47% (over two steps); (f) 4-fluorobenzenesulfonyl chloride,
pyridine, DCM, RT, 15 h, 55%; (g) LiOH, THF, H2O, RT, 2 h, (40%); (h) (1) BOP, DIPEA, DMF, RT, 1 h, 31%; (2) Whelk-O1 (R.R) chiral column.

Scheme 7 Conditions: (a) [(CH3)3COCO]2O, DMAP. CH3CN, RT, 20 h, 95%; (b) LiEt3BH, THF, -78 oC, 30 min.; (c) triethyl phosphonoacetate, NaH, THF,
67% (over two steps); (d) TFA, DCM, 1 h, 99%; (e) hexafluoropropan-2-one, PTSA, 120 oC, 3 h; (f) 4-fluorobenzenesulfonyl chloride, pyridine, DCM, RT,
15 h, 41% over two steps; (g) LiOH, THF, H2O, RT, 15 h; (h) BOP, DIPEA, DMF, RT, 1 h, 67%; (i) Whelk-O1 (R.R) chiral column; (j) Whelk-O1 (R.R)
chiral column, absolute configuration of 55 determined by single crystal X-ray (CCDC # 1586094); (k) (S)-4-amino-3-fluoro-2-methylbutan-2-ol,18 BOP,
DIPEA, DMF, RT, 1 h, 58%.
In conclusion, a HTS screen of the BMS compound collection led to the identification of benzothiazine analog 1, which exhibited
modest activity for RORt but poor selectivity for PXR and LXR/ in cell-based functional assays. We were able to significantly
improve RORt potency while reducing LXR activity by conducting SAR studies at the 2-position of the benzothiazine scaffold.
However, these compounds were still significantly potent at PXR and showed moderate activity at LXR. We solved the X-ray co-
crystal structures of a 2-substituted benzothiazine (25a) with the LBDs of RORt and PXR. Based on these structures, we
developed SAR in a 3-substituted benzothiazine and 2-substituted tetrahydroquinoline series. Representative compound 35
maintained potency at RORt and exhibited markedly improved selectivity for PXR and LXR. Furthermore, compound 35
demonstrated dose-dependent inhibition of IL-17 when tested in vivo in an IL-2/IL-23 induced IL-17 PD model. However, we were
unable to test compound 35 in chronic mouse models of autoimmunity due to significant drop in exposures on repeat dosing in a
mouse PK study, likely due to compound-induced upregulation of Cyp3a11 (mouse 3A4 counterpart). Further work to minimize
the PXR activity and increase RORt potency of this series of RORt inverse agonists is in progress in our laboratories and will be
reported in due course.
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Graphical Abstract
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Identification of Bicyclic Hexafluoroisopropyl
Alcohol Sulfonamides as Retinoic Acid Receptor-
Related Orphan Receptor Gamma
Leave this area blank for abstract info.
(ROR/RORc) Inverse Agonists. Employing
Structure-Based Drug Design to Improve
Pregnane X Receptor (PXR) Selectivity
Hua Gong,a David S. Weinstein,a Zhonghui Lu,a James J.-W. Duan,a Sylwia Stachura,a Lauren Haque,a Ananta
Karmakar,b Hemalatha Hemagiri,b Dhanya Kumar Raut,b Arun Kumar Gupta,b Javed Khan,a Dan Camac,a John
S. Sack,a Andrew Pudzianowski,a Dauh-Rurng Wu,a Melissa Yarde,a Ding-Ren Shen,a Virna Borowski,a Jenny
H. Xie,a Huadong Sun,a Celia D’Arienzo,a Marta Dabros,a Michael A. Galella,a Faye Wang,a Carolyn A.
Weigelt,a Qihong Zhao,a William Foster,a John E. Somerville,a Luisa M. Salter-Cid,a Joel C. Barrish,a Percy H.
Cartera and T. G. Murali Dhar*a