Design, synthesis, and evaluation of simple phenol amides as ERRγ agonists

Article abstract of DOI:10.1016/j.bmcl.2018.03.019

Herein we report the design and synthesis of a series of simple phenol amide ERRγ agonists based on a hydrazone lead molecule. Our structure activity relationship studies in this series revealed the phenol portion of the molecule to be required for activity. Attempts to replace the hydrazone with more suitable chemotypes led to a simple amide as a viable alternative. Differential hydrogen-deuterium exchange experiments were used to help understand the structural basis for binding to ERRγ and aid in the development of more potent ligands.

Full text of DOI:10.1016/j.bmcl.2018.03.019

Accepted Manuscript
Design, synthesis, and evaluation of simple phenol amides as ERRγ agonists
Hua Lin, Christelle Doebelin, Rémi Patouret, Ruben D. Garcia-Ordonez, Mi Ra
Chang, Venkatasubramanian Dharmarajan, Claudia Ruiz Bayona, Michael D.
Cameron, Patrick R. Griffin, Theodore M. Kamenecka
PII:
S0960-894X(18)30198-7
https://doi.org/10.1016/j.bmcl.2018.03.019
BMCL 25673
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
3 January 2018
1 March 2018
6 March 2018
Please cite this article as: Lin, H., Doebelin, C., Patouret, R., Garcia-Ordonez, R.D., Ra Chang, M., Dharmarajan,
V., Bayona, C.R., Cameron, M.D., Griffin, P.R., Kamenecka, T.M., Design, synthesis, and evaluation of simple
phenol amides as ERRγ agonists, Bioorganic & Medicinal Chemistry Letters (2018), doi: https://doi.org/10.1016/
j.bmcl.2018.03.019
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Bioorganic and medicinal chemistry letters
Design, synthesis, and evaluation of simple phenol amides as ERRγ agonists
Hua Lin, Christelle Doebelin, Rémi Patouret, Ruben D. Garcia-Ordonez, Mi Ra Chang,
Venkatasubramanian Dharmarajan, Claudia Ruiz Bayona, Michael D. Cameron, Patrick R. Griffin,
Theodore M. Kamenecka*
The Scripps Research Institute, Scripps Florida, Department of Molecular Medicine, 130 Scripps Way #A2A, Jupiter, FL 33458, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Herein we report the design and synthesis of a series of simple phenol amide ERRγ
agonists based on a hydrazone lead molecule. Our structure activity relationship
studies in this series revealed the phenol portion of the molecule to be required for
activity. Attempts to replace the hydrazone with more suitable chemotypes led to a
simple amide as a viable alternative. Differential hydrogen-deuterium exchange
experiments were used to help understand the structural basis for binding to ERR and
aid in the development of more potent ligands
Available online
Keywords:
Nuclear receptor
ERRγ
2016 Elsevier Ltd. All rights reserved.
Selective ligand
amide
agonist
The nuclear receptor (NR) superfamily of ligand regulated
transcription factors has proven to be a rich source of targets for
the development of therapeutics for a wide range of human
diseases. The NR3B subfamily known as the estrogen-related
receptor (ERRα[NR3B1], ERRβ[NR3B2] and ERRγ[NR3B3])
Although endogenous ligands for the ER’s have shown no
activity at ERRs, some synthetic ligands have demonstrated
activity towards both ER’s and ERRs. Diethylstilbesterol, a
synthetic ER agonist, has been demonstrated to function as an
inverse agonist for all three ERRs.8 4-hydroxytamoxifen, a
synthetic ER antagonist, functions as an inverse agonist of
ERRβ and ERRγ, but displays no activity at ERRα.9,10
regulate
several
physiological
processes,
including
mitochondrial function, glucose and lipid metabolism, and
muscle fiber type determination.1 The ERR’s are constitutively
active orphan nuclear receptors, and while ERRα and ERRβ are
more ubiquitously expressed,1-3 ERRγ is more restricted to
metabolically active and highly vascularized tissues such as
heart, kidney, brain and skeletal muscle.4,5 ERRγ-/- mice fail to
thrive shortly after birth due to abnormal heart and spinal cord
development, but haploinsufficient ERRγ+/- mice are viable and
phenotypically normal in the absence of stress. ERRγ+/- mice
exhibit decreased exercise capacity and muscle mitochondrial
function compared to their WT littermates. In mice, muscle-
specific forced expression of ERRγ increased oxygen
consumption, treadmill endurance, mitochondrial function and
these animals were resistant to diet-induced weight gain.6
Interestingly, repression of ERRγ expression in db/db mice
ameliorated hyperglycemia via inhibition of hepatic
gluconeogenesis. Synthetic modulators of ERRγ including
agonists, antagonists or inverse agonists may hold utility in the
treatment of a myriad of human disorders, including obesity and
type-2 diabetes, cardiovascular disease and muscle atrophy.7
GSK5182 functions as a dual ERRγ /ERα inverse agonist.11,12
A
few ERR selective ligands have also been identified: XCT79013
is an ERRα selective inverse agonist and GSK471614 an
ERRβ/γ selective agonist. Given the receptors specific tissue
distribution and important physiological role, the identification
of ERRγ-selective small molecules would be valuable as
chemical probes and pharmacological tools.
Figure 1
In the search for ERR agonists as in vivo probes, GSK4716
was the only identified agonist reported in the primary literature
(Figure 1). It was discovered via a combination of diversity
screening and structure guided array synthesis. GSK4716 is
>50-fold selective over the classic ERs. Although, GSK4716
can substantially potentiate the transcriptional activity of ERR
with moderate potency, it is far from optimal as an in vivo probe
since it suffers from poor metabolic stability likely due to the
hydrolytically unstable hydrazide moiety.15,16 Additionally, the
phenol group may be subject to phase two metabolism and
The in vivo functions of ERRγ using genetically engineered
mice has provided valuable insight into the in vivo role of ERRγ
in the context of overexpression or depletion of the receptor;
however, pharmacological modulation of ERRγ using selective
small molecule chemical probes would complement and
validate these data in a more translational context.

excretion. Herein we describe our efforts to date to optimize the
potency and metabolic stability of this ligand by modifications
to all portions of the molecule.
better, and the acetamide (SR19539) a bit more active, although
both are partial agonists. Nonetheless, it was quite difficult to
find a suitable replacement for the phenolic group on the
benzoyl ring.
The synthesis of analogs described herein is shown in Scheme
1. Esters
, which were then treated with aldehydes
heating to provide acylhydrazones . The amide compounds
with amines in the
1
were treated with hydrazine to give acylhydrazides
Table 2. 4-tert-Butylphenyl N-acylhydrazones
2
3
under microwave
4
7
were simply obtained by coupling acids
presence of EDCI and HOBt.
5
6
ERR
EC50
(μM)
0.084 19537

ERR
SR
R
SR
R
EC50
(μM)
NA
209906 4-OH
4-OMe
4-CO2H
4-
19822
19552
H
7.6
19638
NA
2-OH
NA
19541
NA
CONHMe
6
(PA)
3.1
19538
19553
3-OH
0.82
19639 4-CONH2
Scheme 1. Synthesis of acylhydrazones and amides
3,4-di-
OH
0.81
(PA)
19539 4-NHAc
Compounds were initially screened in a FRET-based peptide
recruitment assay using -HisSUMO-ERR -LBD, FITC-
RIP140 peptide and a terbium-labelled -HIS antibody. The
(PA)
NA = not active; PA = partial agonist; All assay results are reported as the
arithmetic mean of at least two separate runs.



FRET signal was measured by excitation at 340ꢀnm and emission at
520ꢀnm for fluorescein and 490ꢀnm for terbium using a Perkin Elmer
ViewLux ultra HTS microplate reader. The fold change over DMSO
was calculated by the 520nm/490nm ratio. Graphs were plotted in
GraphPad Prism as fold change of FRET signal for each compound
over DMSO-only control. While the intent was always to find a
suitable replacement for the hydrazone moiety, initial structure-
activity relationship studies (SAR) began with examining both
sides of the N-acylhydrazone to see what groups were tolerated
(Tables 1 and 2). A couple of quick replacement analogs of the
isopropylphenyl ring revealed a 7-fold boost in activity by
incorporating a tert-butyl group at the para-position of the
phenyl ring (SR209906). Other substitutions indicated a need
for something of size at the para-position, as SR205163 was
completely inactive. Naphthyl analog SR9861 was moderately
potent, as was dimethylamine analog SR106447 leaving open
the options for possible substitution patterns down the road.
The last portion of the molecule to investigate was the N-acyl
hydrazone (Table 3). It was unclear whether the N-acyl
hydrazone moiety was simply a linker required to hold in place
the t-butyl phenyl and phenol rings, or whether it was indeed
required for activity. Numerous attempts were made to replace
the hydrazone with other bioisosteres of the same or similar
length, but most led to substantial losses in potency. The only
viable substitution was the simple phenethylamine found in
SR19797. While there is a 10-fold loss in activity, we have
successfully replaced the metabolically labile N-acyl hydrazone
residue with something potentially much more tolerable.
Table 3. Hydrazone replacements
Table 1. 4-hydroxybenzohydrazones as ERR agonists
ERR
EC50

ERR
EC50
SR
R
SR
R
(μM)
(μM)
No.
R
ERR

EC50 (μM)
0.60
209906
0.084
19819
NA
GSK4716
SR209906
SR205163
SR9861
4-iPrC6H4
4-t-BuC6H4
2-FC6H4
2-Naphthyl
4-Me2NC6H4
0.084
NA
2.0
19430
19797
19798
2.3
0.70
NA
19820
19817
19879
NA
NA
NA
SR106447
2.15 (PA)
NA = not active; PA = partial agonist; All assay results are reported as the
arithmetic mean of at least two separate runs.
Given the potency enhancing effect of the 4-tert-butyl group,
this substitution was incorporated into the Eastern portion of the
molecule for further SAR investigations (Table 2). Removal of
the phenol group (SR19822) or moving it from the para-
position to the ortho-position (SR19552) or led to significant
loss of activity. The meta-substituted phenol (SR19538) and the
bis-hydroxy analog SR19553 were both 10 times less potent
than SR209906. Methylation of the phenol (SR19537) was also
not tolerated, indicating a hydrogen bond donor at the para-
position was likely required for activity. A carboxyl group
(SR19638) was not a suitable replacement for the phenol group.
It is perhaps too bulky, or of the wrong pKa. A secondary N-
methylamide (SR19541), is also perhaps too bulky and results
in loss of activity. The primary amide SR19639 is slightly
6.2
(PA)
19818
NA
19640
20739
20248
20121
NA
3.2
4.4

NA = not active; PA = partial agonist; All assay results are reported as the
arithmetic mean of at least two separate runs.
Inspection of the X-ray crystal structure of GSK-4716 with
ERRγ indicates an additional hydrophobic pocket orthogonal to
the binding of the molecule adjacent to the hydrazone amide
group.17 In an attempt to reach this binding pocket and take
advantage of hydrophobic interactions in this region, addition
analogs were prepared incorporating substitution meta to the
phenol group (Table 5). Virtually all attempts at substitution
including dimethylamine, acetamide, methoxy, hydroxyl,
cyanide, florine, trifloromethyl, nitro, different phenyl rings,
and pyridines ledd to loss of activity. The 2-aminosubstituted
compound was slightly more potent as a partial agonist. Its
possible SR19797 which lacks the rigid hydrazone group found
in GSK4716, adopts a slightly different conformation within the
receptor and R-substitution ortho to the amide group cannot
reach this hydrophobic pocket.
Efforts then focused on optimizing SR19797 to build back the
potency lost from replacing the hydrazone linkage (Tables 4 &
5). Similar to the SAR observed in the hydrazone series (Table
2), movement of the para-substituted phenol residue was not
well tolerated. In fact, movement to the ortho-position as in
SR19886 seemed to lead to a switch in pharmacology
conferring ERRγ inverse agonism. The phenol residue could not
be replaced by a phenyl ring (SR20010), 4-pyridyl ring
(SR19889) or aniline (SR19887) without significant loss in
potency. Neither aminopyridine analog (SR19888) or hydroxy-
pyridine analogs (SR20123, 20253) were tolerated nor was a
hydroxy-thiophene analog (SR20255). Benzyl alcohol analog
SR19895 were also inactive, however its isostere SR19894 was
essentially equipotent to SR19797. Attempts to replace the 4-
phenol ring with various indoles were not successful (SR19890,
19891, 19892). The saturated versions of the 4-phenolic group,
4-hydroxy cyclohexane, were not viable replacements
(SR20256, 20257). Finally, substituted phenols were equipotent
to SR19797, when the substitutent was meta to the phenol
group as in SR20011 and 20012, but 10 times less potent when
substituted ortho to the phenol (SR20122, 20338). These results
highlight the importance of the phenol ring hydroxy group to its
activity and its resistance to replacement.
Table 5. Substituted 4-hydroxybenzamides
ERR

ERR
SR
R
SR
R
EC50
(μM)
0.70
0.76
0.95
EC50
(μM)
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
19797
20011
20012
20239
H
CH3
Cl
20252
20238
20244
CN
NO2
C6H5
Table 4. tert-Butyl phenethylamide SAR
NH2
0.30(PA) 20246
2-CH3C6H4
3-CH3C6H4
4-CH3C6H4
20240 Me2N
20241 AcNH
NA
NA
NA
NA
8.9
20242
20237
20243 4-AcNHC6H4
20245 3-AcNHC6H4
20249
20250
20247
20254
20339
20340
MeO
OH
F
ERR
EC50

ERR
EC50
SR
R
SR
R
3-Py
4-Py
(μM)
(μM)
CF3
5.3
NA = not active; PA = partial agonist; All assay results are reported as the
arithmetic mean of at least two separate runs.
19797
19886
0.70
2.9a
19890
19891
NA
Finding it difficult to modify the phenolic ring, we turned our
attention back to the Eastern portion of the molecule (Table 6
and Table 7). Attempts to simplify the molecule by
incorporating simpler amides were not tolerated (SR21580-
21585). Bromine and phenyl substitutions were not viable
replacements for the tert-butyl group and led to loss of activity
(SR19878, 19884). The more rigid amide (SR19885) was not
active although it also lacked para-substitution. Shortening the
linker between the amide and phenyl ring by one carbon atom
(SR19879) led to loss of activity, whereas a one carbon
extension led to ~6x drop in potency (SR20739).
Unexpectedly, the one carbon extension in a compound lacking
the tert-butyl group was only 2-fold less potent than the lead, so
there may be room for additional modifications here
(SR19887). Attempts to shorten the linker between the amide
nitrogen atom and the phenyl ring, at the same time increasing
the length of the substituent at the para-position of the phenyl
ring wasn’t tolerated (SR20118, 20119). However, rigidifying
the linker in the amide side chain by incorporating it into a ring
NA
20010
7.9(PA) 19892
NA
19889
19887
NA
9.1
20256
20257
NA
NA
19888
20123
NA
NA
20120
20122
NA
6.2
20253
20255
19895
19894
NA
NA
NA
0.95
20338
20011
20012
7.0
led to
a compound with similar potency to SR19737
(SR20043).
0.76
0.95
Table 6. Eastern Portion - Amide SAR
ERR
EC50

ERR
SR
R
SR
R
EC50
a inverse agonist; NA = not active; PA = partial agonist; All assay results are
reported as the arithmetic mean of at least two separate runs.
(μM)
(μM)

21580
21581
NA
NA
19885
19879
NA
NA
20038
1.14
20039
NA
1.71(
PA)
21582
21583
NA
NA
20739
19887
4.4
1.3
19883
20007
20737
20738
4.3
5.9
3.0
NA = not active; All assay results are reported as the arithmetic mean of at least
two separate runs
21584
21585
NA
NA
20118
20119
20043
NA
NA
1.3
The lead hydrazone GSK4716 was reported to be an ERR
/-
selective agonist with no activity at ERR . To confirm

selectivity was maintained in this series, a few best-in-class
molecules were counterscreened in a FRET-based peptide
recruitment assay using either
HisSUMO-ERR -LBD, FITC-RIP140 peptide and a terbium-
labelled -HIS antibody (data not shown). All analogs tested
(GSK4716, SR19797, SR19881, SR19894, SR20041,
-HisSUMO-ERR-LBD or -
19878
19884
NA
NA


SR20043) showed no activity vs ERR
more interesting. GSK4716 is 5-fold less potent on ERR
on ERR (ERR EC50=3.0
slight preference for ERR
EC50=0.63 M; SR19894 ERR
showed increased selectivity (7-8-fold) for ERR

. Activity vs ERR

was
than

NA = not active; All assay results are reported as the arithmetic mean of at least
two separate runs



M). SR19881 and SR19894 show a
vs ERR (SR19881 ERR
EC50=2.7 M). Other analogs
vs ERR
ERR
M). Finally, SR20011 and SR20012 showed 30-
vs ERR (SR20011 ERR EC50=
EC50= 0.031 M). These data may
pave the way to designing truly (>100-fold) ERR -selective and
ERR -selective agonists.






Given that dimethylamine substitution was tolerated as in
SR106447 (Table 1), we investigated hydrophobic amine
substitutions as replacements for the tert-butyl group (Table 7).
Cyclic amines (SR19880, 19882) or simple mono-substituted
anilines (SR20037) were not active, nor was an acetylated
version (SR20039). The slightly bulkier diethylamine variant
(SR19881) is twice as potent as the tert-butyl varient (SR19797)
and the most potent full agonist identified in our SAR studies.
Increasing the size of the alkyl substituents on the nitrogen led
to some analogs with modest potency (SR20038, 19883, 20042,
20007), but too big, and potency was lost (SR20043, 20044).
The isobutyl ethylamine substituted analog SR20041 was very
potent, but as a partial agonist. Incorporation of a halogen ortho
to the para-amine group (SR20737, 20738) was not tolerated
and led to a 10-fold drop in potency.



(SR19797
ERR
EC50=0.090

M;
SR20239
EC50=0.045

40-fold selectivity for ERR
0.020 M; SR20012 ERR








To further confirm pharmacology of the compounds in vitro,
GSK4716 and SR19797 were screened in HEK293T cells in a
Gal4-ERRγ::UAS-Luc reporter assay with counterscreening
against Gal4-VP16::UAS-Luc. Concentration-response curves
(CRCs) are shown in Figure 2. Both compounds present as
agonists in this cell-based assay, but GSK4716 exhibits some
non-specific activation of VP16 which might be contributing to
its activity whereas SR19797 does not.
Table 7. p-Amino substitutions
19797
GSK4716
3
2
1
0
8
6
4
2
0
Gal4 hinge ERRG LBD
Gal4 hinge VP16 LBD
Gal4 hinge ERRG LBD
Gal4 hinge VP16 LBD
ERR
EC50
(μM)

ERR
SR
R
SR
R
EC50
(μM)
-10
-9
-8
-7
-6
-5
-4
-10
-9
-8
-7
-6
-5
-4
Conc of [Log Scale, M]
Conc of [Log Scale, M]
Gal4 hinge ERRG LBD Gal4 hinge VP16 LBD
EC50 4.701e-006 27.53
Gal4 hinge ERRG LBD Gal4 hinge VP16 LBD
EC50 1.899e-006 2.726e-007
19880
NA
NA
NA
0.39
20042
3.5
NA
NA
Figure 2. In vitro characterization of synthetic ERRγ agonist.
To better understand the structural basis of binding of lead SR19797
and the diethylamine analog SR19881 to ERRγ, we performed
differential hydrogen/deuterium exchange (HDX) mass spectrometry
(Figure 3) using purified ERRγ ligand binding domain (LBD). HDX
data show a clear difference in structural perturbations between the
apo receptor and the liganded complexs indicating that both
SR19797 and SR19881 bind to the LBD. HDX revealed that helix 11
and helix 12 regions show increased protection from solvent
exchange (interpreted as stabilization, in green) with both ERRγ
ligands tested, suggesting common sites of interaction within the
ligand-binding pocket (LBP) of ERRγ. Moreover, presence of the
diethylamine substituent (H-bond acceptor) in SR19881 but not the
parent compound (SR19797), showed additional protection in helix 2
19882
20037
19881
20043
20044
20041
0.21(
PA)

4.
Eudy, J.D. Yao, S.; Weston, M. D.; Ma-Edmonds, M.; Talmadge,
C. B.; Cheng, J. J.; Kimberling, W. J.; Sumegi, J. Genomics 1998,
50, 382.
and β-sheet regions indicating ancillary hydrogen bond interactions
that likely contributes to its increased binding potency.
5.
6.
Jagannath M.; Kim, D. -K.; Choi, H.-S., Trends Endocrin. Met.
2017, 28, 261.
Narkar, V. A.; Fan, W.; Downes, M.; Yu, R. t.; Jonker, J. W.;
Alaynick, W. A.; Banayo, E.; Karunasiri, M. S.; Lorca, S.; Evans,
R. M. Cell Metab. 2011, 13, 283.
Figure 3. HDX analysis of selected ERR agonists
7.
8.
9.
Yang, X.; Downes, M.; Yu, R. T.; Bookout, A. L.; He, W.;
Straume, M.; Mangelsdorf, D. J.; Evans, R. M. Cell 2006, 126,
801.
Tremblay, G. B.; Kunath, T.; Bergeron, D.; Lapointe, L.;
Champigny, C.; Bader, J-A.; Rossant, J.; Giguère, V. Genes. Dev.
2001, 15, 833.
Coward, P.; Lee, D.; Hull, M. V.; Lehmann, J. M. PNAS. 2001,
98, 8880.
10. Tremblay, G. B.; Bergeron, D.; Giguere, V. Endocrinology 2001,
142, 4572.
SR-19797
SR-19881
11. Chao, E. Y. H.; Collins, J. L.; Gaillard, S.; Miller, A. B.; Wang, L.
P.; Orband-Miller, L. A.; Nolte, R. T.; McDonnell, D. P.;
Willson, T. M.; Zuercher, W. J. Bioorg. Med. Chem. Lett. 2006,
16, 821.
Selected compounds were tested for stability in human, rat and
mouse liver microsomes (Table 8). All analogs inlcuding GSK4716
had short half-lives. Nonetheless, we have successfully replaced the
acylhydrazone linkage with a saturated amide and maintained
potency and comparable metabolic stability to the lead GSK4716.
The phenethyl linkage is likely a metabolic soft spot in the saturated
analogs. We will continue to explore substitutions here to improve
stability. While not necessarily important to microsomal stability, the
phenol group will likely be subject to phase 2 metabolism. Future
SAR efforts will continue to search for suitable replacements for the
phenol group to reduce this liability.
12. Kim, J.; Chin, J.; Im, C. Y.; Yoo, E. K.; Woo, S.; Hwang, H. J.;
Cho, J-H.; Seo, K.; Song, J.; Hwang, H.; Kim, K-H.; Kim, N. D.;
Yoon, S. K.; Jeon, J-H.; Yoon, S-Y.; Jeon, Y. H.; Choi, H-S.; Lee,
I-K.; Kim, S. H.; Cho, S. J. Eur. J. Med. Chem. 2016, 120, 338.
13. Busch, B. B.; Stevens, W. C. Jr.; Martin, R.; Zhou, S.; Sapp, D.
W.; Horlick, R. A.; Mohan, R. J. Med. Chem. 2004, 47, 5593.
14. Zuercher, W. J.; Gaillard, S.; Orband-Miller, L. A.; Chao, E. Y.
H.; Shearer, B. G.; Jones, D. G.; Miller, A. B.; Collins, J. L.;
McDonnell, D. P.; Willson, T. M. J. Med. Chem. 2005, 48, 3107.
15. Bhat, V. T.; Caniard, A. M.; Luksch, T.; Brenk, R.; Campopiano,
D. J.; Greaney, M. F. nat. chem. 2010, 2, 490.
16. Ji, K.; Lee, C.; Janesko, B. G.; Simanek, E. E. Mol. Pharmaceutics
2015, 12, 2924.
17. Wang, L.; Zuercher, W. J.; Consler, T. G.; Lambert, M. H.; Miller,
A. B.; Orband-Miller, L. A.; McKee, D. D.; Willson, T. M.; Nolte,
R. T. J. Bio. Chem. 2006, 281, 37773.
Table 8: Metabolic stability
Half life in 1 mg/ml heptatic microsomes
Species (T1/2 in minutes)
Compound ID
GSK4716
SR20041
SR20012
SR20011
SR19881
SR19797
Human
6.4
3.0
2.9
3.6
Mouse
2.3
1.6
1.2
1.5
Rat
2.2
1.5
1.1
1.5
3.9
1.6
3.1
6.8
2.2
3.3
In summary, we have identified a series of amides as ERRγ
agonists with suitable potency for further development. Our
SAR studies of this chemotype identified SR19881 as the most
potent full agonist of ERRγ with an EC50=0.39 μM in a binding
assay and an EC50=4.7
also equipotent on ERR
equipotent dual agonist of ERR/


M in a cell-based assay. SR19881 was
with an EC50=0.63 μM making it an
. HDX studies help explain
how subtle changes to the molecule translate into improved
potency by increased stabilization of the receptor. These studies
provided valuable information and an opportunity to expand the
series in search of more potent, selective, and druglike
molecules. Further investigations of new chemotypes and
pharmacokinetic properties continue in an effort to explore the
role of ERRγ in vitro and in vivo. These results will be reported
in due course.
Acknowledgments
This work was supported by the Eunice Kennedy Shriver National
Institute of Child Health & Human Development (HD087046 to
P.R.G and T.M.K.).
References and notes
1.
2.
3.
Giguère, V. Endocr. Rev. 2008, 29, 677.
Audet-Walsh, E; Giguère, V. Acta. Pharmacol. Sin. 2015, 36, 51.
Huss, J. M.; Garbacz, W. G.; Xie, W. Biochim. Biophys. Acta.
2015, 1852, 1912.