Development of a novel NURR1/NOT agonist from hit to lead and candidate for the potential treatment of Parkinson's disease

Article abstract of DOI:10.1016/j.bmcl.2019.01.024

In the course of a programme aimed at identifying Nurr1/NOT agonists for potential treatment of Parkinson's disease, a few hits from high throughput screening were identified and characterized. A combined optimization pointed to a very narrow and stringen

Full text of DOI:10.1016/j.bmcl.2019.01.024

Accepted Manuscript
Development of a novel NURR1/NOT agonist from hit to lead and candidate
for the potential treatment of Parkinson's disease
Dominique Lesuisse, André Malanda, Jean-François Peyronel, Yannick
Evanno, Patrick Lardenois, Danielle De-Peretti, Pierre-Yves Abécassis, Pascal
Barnéoud, Pascale Brunel, Marie-Claude Burgevin, Céline Cegarra, Florian
Auger, Amélie Dommergue, Corinne Lafon, Luc Even, Joanna Tsi, Thy Phuong
Hieu Luc, Antonio Almario, Anne Olivier, Marie-Noëlle Castel, Véronique
Taupin, Thomas Rooney, Xavier Vigé
PII:
S0960-894X(19)30033-2
https://doi.org/10.1016/j.bmcl.2019.01.024
BMCL 26261
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
23 October 2018
12 January 2019
17 January 2019
Please cite this article as: Lesuisse, D., Malanda, A., Peyronel, J-F., Evanno, Y., Lardenois, P., De-Peretti, D.,
Abécassis, P-Y., Barnéoud, P., Brunel, P., Burgevin, M-C., Cegarra, C., Auger, F., Dommergue, A., Lafon, C.,
Even, L., Tsi, J., Luc, T.P.H., Almario, A., Olivier, A., Castel, M-N., Taupin, V., Rooney, T., Vigé, X., Development
of a novel NURR1/NOT agonist from hit to lead and candidate for the potential treatment of Parkinson's disease,
Bioorganic & Medicinal Chemistry Letters (2019), doi: https://doi.org/10.1016/j.bmcl.2019.01.024
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Development of a novel NURR1/NOT agonist from hit to lead
and candidate for the potential treatment of Parkinson's disease
Dominique Lesuissea*, André Malandab, Jean-François Peyronelb, Yannick Evannob,
Patrick Lardenoisb, Danielle De-Perettib, Pierre-Yves Abécassisc, Pascal Barnéouda,
Pascale Bruneld, Marie-Claude Burgevine, Céline Cegarraa, Florian Augerb, Amélie
Dommergueb, Corinne Lafonf, Luc Evenb, Joanna Tsib, Thy Phuong Hieu Lucb, Antonio
Almariob, Anne Oliviere, Marie-Noëlle Castelg, Véronique Taupina, Thomas Rooneya,
Xavier Vigée
a Rare and Neurologic Disease Research, Sanofi, 1 av Pierre Brossolette, Chilly Mazarin, F-91935, France
b Medicinal chemistry, Sanofi, 1 av Pierre Brossolette Chilly Mazarin, F-91935, France
c
DSAR , Sanofi, 13 quai Jules Guesde Vitry-sur-Seine F-94403, France
Preclinical safety , Sanofi, 3, digue d’ Alfortville Alfortville F- 94140, France
d
e Translational Science, Sanofi , 1 av Pierre Brossolette, Chilly Mazarin, F-91935, France.
f CNS Department, Sanofi, 195 route d’Espagne, F-31036 Toulouse, France.
g CNS Department, 13, quai Jules Guesde, F-94403 Vitry-sur-Seine Cedex, France.
Development of a novel NURR1/NOT agonist from hit to lead and candidate for the potential treatment of Parkinson's
disease
Dominique Lesuisse*, André Malanda, Jean-François Peyronel, Yannick Evanno, Patrick Lardenois, Danielle De-Peretti, Pierre-
Yves Abécassis, Pascal Barnéoud, Pascale Brunel, Marie-Claude Burgevin, Céline Cegarra, Florian Auger, Amélie Dommergue,
Corinne Lafon, Luc Even, Joanna Tsi, Thy Phuong Hieu Luc, Antonio Almario, Anne Olivier, Marie-Noëlle Castel, Véronique
Taupin, Thomas Rooney, Xavier Vigé
In the course of a programme aimed at identifying Nurr1/NOT agonists for potential treatment of Parkinson’s disease, a few hits from high
throughput screening were identified and developed into initial leads 3 and 4. A comprehensive program of optimization led to a potent and
safe candidate drug 38 displaying neuroprotective and anti-inflammatory activity in several in vitro and in vivo models.
O
N
N
N
N
H
N
3
Cl
N
HO
N
Cl
38
N
HO
4
Abstract: In the course of a programme aimed at identifying Nurr1/NOT agonists for potential treatment of Parkinson’s disease, a few
hits from high throughput screening were identified and characterized . A combined optimization pointed to a very narrow and stringent
structure activity relationship. A comprehensive program of optimization led to a potent and safe candidate drug displaying
neuroprotective
and
anti-inflammatory
activity
in
several
in
vitro
and
in
vivo
models.
Parkinson’s disease is a devastating neurodegenerative
disease that will affect 1 person out of 100 at 60 years (7
to 10 million worldwide)1. Dopaminergic neurons are
mostly affected resulting in less dopamine and less
activation of motor neurons in the central nervous
system. The nuclear receptor Nurr1 has been shown to be
essential to the development and survival of
dopaminergic neurons in the substantia nigra and VTA2.
Nurr1 KO mice display increased vulnerability to MPTP3
and age-dependent dopaminergic dysfunction4.
In
addition, NOT (human gene) polymorphisms have been
reported in Parkinson’s disease5. Nurr1 is an orphan
*Corresponding author Tel : 33 1 60496857; email: dominique.lesuisse@sanofi.com

receptor, no endogenous ligand has been identified to-
date and it has even been reported as a class of ligand-
independent nuclear receptors6. This paper describes a
combined medicinal chemistry effort that led to the
identification of a potent imidazopyridine NOT agonist
and allowed us to uncover some of its neuroprotective
potential.
In parallel, the effects of Nurr1/NOT agonists on the
production of the pro-inflammatory cytokine IL-1 were
assessed in LPS-treated MG7 mouse microglia cell line.
Results are summarized in table 2.
Table 2: In vitro cellular activities of compounds 3 and 4.
Assays
3
4
TH expression (% increase)
IL-1β secretion in MG7
(%inhibition)
174-216 @3 µM
Not done
188-313 @3 µM
58 % @ 3 µM
Screening was performed on
a
CHO cell line
LPS-Induced Neurotoxicity
(% of neuroprotection)
Not done
37% @ 3µM
65% @10 µM
overexpressing a fusion protein of full length NOT with
a Gal4 DNA binding domain and a Gal4 response
element coupled with luciferase and, a neuronal N2A cell
line containing endogenous mouse Nurr1 stably
transfected with NBRE coupled to luciferase reporter
gene. Strikingly, the screening on both cell lines led to
very similar hits belonging to the bicyclic
imidazopyridines series of general structures 1 and 2.
Before evaluating the activity in in vivo pharmacological
models, a full ADMET and PK exploration of these two
leads was undertaken. Both displayed very poor
solubilities and high clearance. In addition, hErg channel
activation at low concentration was recorded for
compound 4 (Table 3).
Ar
N
N
R
Ar (HetAr)
R
N
N
Table 3 : ADMET and PK properties of compounds 3 and 4
O
Property
Solubility
Plasma
stability
Lipophilicity
pKa
Permeability
Metabolism
Clearance
Parameter
HPLC
Human/mouse
3
4
1
2
<1 µM
Stable/unstable
<1µM
Stable/stable
From there, optimization was conducted to give the two
potent Nurr1/NOT agonists 37 and 48 (Table 1).
LogD/PSA
3.65/59
3.6
High
21/20
Mod/High
(0.128)
2.95/38
5.16
High
8/22
High (0.42)
Table 1 : In vitro Nurr1/NOT activities of compounds 3 and 4
Caco2 (Papp)
%(mouse/human)
Human
O
N
N
Cl
N
N
N
N
H
HO
3
4
hepatocytes
(mL.hr-1.10-6 cells)
Brain/Plasma AUC
3A4/2D6/2C9
(IC50 µM)
EC50 (nM)
Emax (%)
204
EC50 (nM)
Emax (%)
240
N2A cells
CHO cells
1
140
1
75
BBB
CYP inhibition
1.6
>10/>10/8.6
2.9
>10/>10/8.6
203
239
CYP induction
Cardiotoxicity
Genotoxicity
% of Emax
hErg (EC50 µM)
Ames, MNT, Fetax
None (<20%)
>10
Negative
None (<20%)
0.9
Negative
The synthesis of the two compounds is straightforward
using classical chemistry reported for synthesis of
imidazo[1,2a]pyridines9 (scheme 1). The 4-iodo- or 4-
bromoaminopyridines 5 and 6 were condensed with the
bromooxalate and bromoketones 7 and 8 to produce the
bicyclic imidazopyridines 910 and 10, respectively.
Anilide formation and pyridine stannane coupling on 9
and hydroxymethylphenylboronic acid Susuki coupling
on 10 led to 3 and 4, respectively.
When analyzing the specific metabolism of 3, even
though it was not metabolized in human plasma or liver
microsomes, the finding that it gave rise to amide
hydrolysis with aniline release in mice microsomes
(scheme 2) was of major concern in view of the known
genotoxicity of aniline and some of its derivatives.
B(OH)2
Mice liver
microsomes
O
N
N
O
N
HO
Cl
N
H2N
+
N
N
N
N
OH
Br
N
H
10
11
3
Pd[P(Ph)3]4 /Na2CO3
Toluene/CH3CN/150°C
77 %
N
Aniline
BrCH2COPh-4-Cl
8
Cl
N
Scheme 2
X=Br
NaHCO3
HO
nButanol
MeTHF
88 %
4
As it has been reported that some substituted anilines are
devoid of mutagenicity11, we synthesized a series of
analogs of 3 varying on one hand by the substitution of
the aryl group. Surprisingly the activity on the receptor
was lost in almost all analogs in the CHO cell line while
activation (Emax) was very weak in the N2A cell line
(Table 4). Only the N-(6-fluoropyridin-2-yl) derivative
20 kept some activity in both screening cell lines;
however it turned out inactive in the TH assay.
X
NH2
N
O
N
X = I
X = Br 6
5
1. PhNH2 / Me3Al
Toluene
2.
N
N
N
H
7
BrCOCOOEt
X=I
NaHCO3/nButanol
3
N
Sn(Bu)3
THF 65%
O
N
PPh3/DMF
100-150°C
N
OEt
I
85%
9
Scheme 1
Table 4: Modifications of the anilide portion of 3
Several assays were developed in order to assess the
potential of these new compounds on both
neuroprotection and inflammation in models related to
O
N
N
N
N
H
Aryle
Parkinson’s disease.
A rat mesencephalic primary
Cpd
Aryle
EC50 N2A Emax N2A EC50 CHO Emax CHO
(nM)
1
2,5
(%)
204
85
(nM)
140
>1000
(%)
203
nd
neuronal model was used to evaluate the impact of the
agonists on tyrosine hydroxylase (TH) expression. In
vitro neuroprotection was evaluated in a co-culture of
mouse primary neurons and microglia treated with LPS.
3
12
Ph
Ph(3,5-F2)
13
14
Ph(2-Cl)
Ph(3-F)
26,5
1
68
103
>1000
>1000
nd
nd

15
16
17
18
19
20
21
22
Ph(2-F)
Ph(2,5-F2)
Ph(2,3-F2)
Ph(2-CN)
Py(2)
Py(2)(6-F)
Thienyl(3)
Thiazole(2)
1
1
1,2
292
2
0,6
1
0,8
104
68
64
52
87
86
85
72
>1000
>1000
>1000
>1000
>1000
25
nd
nd
nd
nd
nd
138
nd
nd
activity in the CHO Gal4 assay (cpd 35).
enantiomers were separated (cpds 36 & 37) and the most
active (cpd 36) again showed a high hepatocyte clearance
The
not predicted by microsomal metabolism.
Any
substitution other than methyle (ethyle, butyle, pentyle,
hexyle, iButyle, cyclopentyle, phenyle) abolished the
activity (Supplement Table 2). Addition of a second
methyl group led to compound 38 with acceptable
activity and with a solved clearance issue. With the
exception of oxetanyl 39 all other disubstitutions gave
rise to inactive compounds (cpds 40-41) (Table 6).
>1000
>1000
23
Isoxazole(3)
20
67,6
21
62
70
61
85
>1000
>1000
>1000
>1000
nd
nd
nd
nd
24 Thiadiazole(2)
25
26
Pyrrazole(3)
Isoxazole(4)
55
Replacements of the anilide by heteroaryls such as
tetrahydropyridine or indoline in 27 and 28 gave rise also
Table 6: Modifications on the hydroxymethyl group of 4
to inactive compounds.
stopped.
Therefore this series was
N
OH
Cl
R2
R3
N
O
N
N
O
N
N
N
N
N
N
Cpd
R2
R3
HEP
clearance
0.42
Comment
EC50
CHO
28
27
4
45 ± 14
99 ± 24
75 ± 45
219 ± 174
218 ± 38
323 ± 86
>1000
H
H
H
H
H
Me
35
36
37
38
39
40
41
Me
Me
Me
Me
rac
(+)
(-)
The second lead 4, even though not metabolized in liver
microsomes, displayed non-CYP450-mediated
0.45
a
oxidation (most probably NAD oxidase-dependent) when
profiled in human hepatocytes, leading to fast formation
0.051
CH2OCH2
(CH2)2O(CH2)2
Me CH2OH
of the inactive carboxylic acid metabolite 29 (scheme 3).
>1000
N
N
O
Cl
Cl
NAD oxidase
N
N
HO
HO
The initial lead 4 displayed hErg inhibition (IC50=0.9
µM) not compatible with chronic long term treatment.
Therefore, throughout the above optimization this
parameter was also closely monitored. Unfortunately,
the optimized lead 38 still displayed hErg inhibition
(IC50=1.5 µM). As the difluorinated analog 31 showed
reduced hErg activity, compound 42, combining
substitutions of 38 and 31, was synthesized. However,
this compound did not show reduced hErg activity and
lost its activity on the target (Figure 1).
4
29
Scheme 3
Classical medicinal chemistry on lead 4 did not allow
correcting of these liabilities. Hindering the primary
alcohol by introducing substitution on the aryl group was
undertaken (Table 5). Addition of a fluorine atom in
ortho positions of the hydroxymethylene permitted to
keep the activity (CHO assay), however the hepatic
clearance remained unacceptable (cpds 30 & 31).
Strikingly, one of the ortho positions was not tolerated
with a single fluorine atom (cpd 32) while disubstitution
permitted to keep the activity (cpd 31). We have no
explanation for this result. By contrast, activity was
totally lost when a methyl group was introduced in both
ortho positions (cpds 33 &34).
N
OH
PhCl
N
4
CHO 45 nm
hErg 0.9 µM
N
F
N
OH
N
OH
PhCl
OH
F
F
PhCl
N
PhCl
N
N
F
Table 5: Hindering of the hydroxymethyl group of 4
R1
42
N
38
31
CHO 38 nM
hErg 24%@10µM
OH
Cl
CHO >1000 nM
hErg 70%@10µM
CHO 218 nM
hErg 1.5 µM
N
R2
Figure 1
EC50 CHO
(nM)
HEP clearance
(mL.hr-1.10-6 cells)
0.42
Cpd
R1
R2
4
45 ± 14
14 ± 2
38 ± 20
>1000
>1000
>1000
H
F
F
H
H
H
H
F
F
Me
H
Since the discovery of a link between drug-induced
hERG inhibition and cardiac safety related to Torsade de
Pointes (TdP)12, this parameter has become one of the
essential counter screening parameters leading to
elimination of hERG inhibitors. However, for some
medicinal chemistry targets such as kinases where the
binding site combines lipophilicity, flatness and the need
for basic nitrogens, totally eliminating hErg activity
might become a real challenge. Any attempts we made
to modulate the pKa of lead 4 scaffold by removing or
adding nitrogen atoms such as in compounds 43-46
totally abolished the activity (CHO assay) (Figure 2).
30
31
32
33
34
0.188
0.13675
Me
Replacements for the hydroxymethyl by a variety of
alcoxy- or alkylamino-methyl, amides (with the
exception of primary methyl amide) or cyano groups led
to total loss of activity showing a stringent need for a
hydrogen bond donor group at this position (Supplement
Table 1). We therefore focused on modifications while
keeping the hydroxyl group in place. Here the space was
again strikingly narrow as only the methyl group was
tolerated as a substituent (Table 6). Addition of one
methyl on the hydroxymethyl group led to comparable

N
N
OH
Compound 38 demonstrated in vivo anti-inflammatory
activity in a LPS-induced TNF- release model, with a
47% inhibition of serum TNF- at 30mg/kg (supporting
information). It was also shown to induce dopamine
neuroprotection and to reduce brain gliosis and IL-6
levels in a Parkinson’s Disease lesion model induced by
inflammatory stimulant Poly(I:C)15.
PhCl
OH
N
PhCl
N
N
OH
PhCl
N
44
Inactive
43
Inactive
4
N
CHO 45 nm OH
N
N
PhCl
OH
N
N
PhCl
N
N
46
45
Inactive
Inactive
A few hits from an HTS were characterized as agonists
of the NURR1/NOT receptor. Combined optimization
pointed to a very narrow and stringent structure activity
relationship and led to a potent candidate displaying
neuroprotective and anti-inflammatory activities in
several in vitro and in vivo models. During this work, we
prioritized compounds that were active on both CHO
and N2A cell lines. CHO cell line overexpressing NOT
as a fusion protein coupled to Gal4 only selects agonists
of homodimeric receptor, while N2A cell line relying on
endogenous expression of mouse Nurr1 has the potential
to unveil agonists of both homodimeric or heterodimeric
receptors. Recent evidence suggests that the dimeric
transcription factor Nurr1/retinoid X receptor (RXR) is a
key player in anti-inflammatory and neuroprotective
activities16. Some of the compounds reported here could
also be dual agonists but this was not looked at. A few
reports describing NURR1 or NOT agonists can be found
in the literature17,18 however it is not clear whether any of
these compounds are actively developed. Unlike some of
the reported agonists of these receptors, our series offer
the advantage of having no polar function preventing
access to the brain.
Figure 2
However, it has been shown that hErg is not always
predictive of proarrhythmic risk. For example, it has
been shown that Clomiphene, a potent hErg inhibitor,
does not display a significant QT effect in the perfused
heart of guinea pig13. Discrepancies have been proposed
to be related to different binding kinetics in the hErg
channel.14 As compound 38 displayed a good brain PK
profile (Table 7) along with a safe profile on other
parameters, such as CYP (inhibition and induction) and
selectivity vs a panel of GPCR and nuclear receptors, it
was decided to further investigate its potential cardiac
liabilities.
Importantly, compound 38 showed no
significant hemodynamic, electrocardiographic or
electrophysiological effect after single 5-min iv
administration in anaesthetized guinea pigs and dogs
despite high heart exposure in both species (up to 17 and
40 µM total concentrations in guinea pig and dog
respectively (supporting information).
Table 7: Pharmacokinetic parameters following single IV (3 mg/kg)
and oral (10 mg/kg) administration of 38 to female C57BL/6 mice.
Brain
/plasma
AUC ratio
C0 or
Cmax
Acknowledgements
We are grateful to the analytical department for
compound analyses and enantiomers separation.
Route Matrix
Dose
tmax
AUC
CL
Vss
t1/2z
(mg/kg) (µg/mL) (day) (µg.h/mL) (L/(h.kg)) (mL/kg) (day)
(%)
iv Plasma
3
3
4.87
2.63
4.17
3.08
-
20.6
15.0
70.3
55.6
0.1
0.9
4.1
3.8
8.1
8.2
iv
Brain
References and Notes
po Plasma 10
po Brain 10
1
8
0.7
0.8
1
Tansey, M. G., Goldberg, M. S. (2010).
Neuroinflammation in Parkinson's disease: Its role in
neuronal death and implications for therapeutic
intervention. Neurobiology of Disease, 37(3), 510-518.
doi: 10.1016/j.nbd.2009.11.004
The synthesis of 38 was straightforward (scheme 4).
From 10, Suzuki coupling followed by Grignard reaction
afforded a high yield of 38.
1)
B(OH)2
2
O
Zetterström, R.H., Solomin, L., Jansson, L., Hoffer,
N
N
Cl
N
B.J., Olson, L., Perlmann,T., (1997) Dopamine neuron
agenesis in Nurr1-deficient mice. Science Science,
276,248–250. doi: 10.1126/science.276.5310.248
Cl
HO
N
Br
MeTHF / eau / Na2CO3
FibreCat 1032
(polypropylene-supported
Pd complex)
38
10
77%
3 Le, W.D., Conneely, O.M., He, Y., Jankovic, J., Appel,
S.H., (1999). Reduced Nurr1 expression increased the
vulnerability of mesencephalic dopaminergic neurons to
MPTP-induced injury. J. Neurochem,73, 2218–2221.
doi:10.1046/j.1471-4159.1999.02218.x
2) MeMgBr/Toluène /THF
94 %
Scheme 4
Compound 38 displayed good neuroprotective and anti-
inflammatory activity in vitro in several assays and
increased the expression of TH in rat mesencephalic
dopaminergic neurons (Table 8).
4
Jiang, C., Wan, X., He, Y., Pan, T., Jankovic, J., Le,
W., (2005). Age-dependent dopaminergic dysfunction in
Nurr1 knock-out mice. Exp. Neurology, 191, 154-162.
doi: 10.1016/j.expneurol.2004.08.035
5
Zheng, K., Heydari, B., Simon, D.K., (2003). A
Table 8: In vitro cellular activities of compound 38 at 3µM.
common NURR1 polymorphism associated with
Parkinson disease and diffuse Lewy body disease. Arch
Neurol. 60, 722–725. doi: 10.1001/archneur.60.5.722
TH expression (% increase)
188-284
28-46
IL-1 secretion in MG7 (% inhibition)
LPS-induced neurotoxicity (% of neuroprotection)
86-99

17
6 Wang, Z., Benoit, G., Liu, J., Prasad, S., Aarnisalo, P.,
Liu, X., Xu, H., Walker N. P. C., Perlmann, T. (2003)
Structure and function of Nurr1 identifies a class of
ligand independent nuclear receptors, Nature, 423 , 555-
60. doi: 10.1038/nature01645
Dubois, C., Hengerer, B., Mattes, H. (2006)
Identification of a Potent Agonist of the Orphan Nuclear
Receptor Nurr1, ChemMedChem, 1, 955 – 958. doi:
10.1002/cmdc.200600078
18 Kim, C.-H., Leblanc, P., Kim, K.-S. (2016) 4-amino-7-
chloroquinoline derivatives for treating Parkinson’s
disease: implications for drug discovery, Expert Opinion
7
Peyronel, J.F. Derivatives of 6-heterocyclic
imidazo[1,2a]pyridines2-carboxamides,
WO 2009106750 A2 ; Peyronel, J.F. Derivatives of N-
heterocyclic-6-heterocyclic-imidazo[1,2a]pyridines-2-
carboxamides WO2009106751 A2.
on
Drug
Discovery,
11(4),
337-341.
doi:
10.1517/17460441.2016.1154529
8
Almario, G.A., Lardenois, P., Olivier, A.,
WO 2008034974 A1; De-Peretti, D., Evanno, Y.,
Polysubstituted
derivatives
of
2-aryl-6-phenyl-
imidazo[1,2a] pyridine, WO2009144391 A1.
9
Teulade, J.-C., Gueiffier, A., Chapat, J.-P., Grassy, G.,
Carpy, A., H’Naifi, A., Perly, B., Couquelet, J. (1989)
Studies on the imidazo[1,2a]pyridinic system : Synthesis
of pyrido[1’2’ :1,2]imidazo[5,4-d][1,3]-benzodiazepines.
Chem. Pharm. Bull. 37 (9) 2293-2297. doi:
10.1248/cpb.37.2293
10
Sundberg, R. J.; Biswas, S.; Murthi, K. K.; Rowe, D.;
McCall, J. W.; Dzimianski, M. T. (1998) Bis-Cationic
heteroaromatics as macrofilaricides: synthesis of bis-
amidine and bis-guanylhydrazone derivatives of
substituted Imidazo[1,2-a]pyridines, Journal of Medicinal
Chemistry, 41(22), 4317-4328. doi : 10.1021/jm9803368
11
Kugler-Steigmeier, M. E.; Friederich, U.; Graf, U.;
Lutz, W. K.; Maier, P.; Schlatter, C. (1989),
Genotoxicity of aniline derivatives in various short-term
tests. Mutation Research, Fundamental and Molecular
Mechanisms of Mutagenesis, 211(2), 279-89; doi :
10.1016/0027-5107(89)90011-0
12
Wallis, R. M. (2010), Integrated risk assessment and
predictive value to humans of non-clinical repolarization
assays, British Journal of Pharmacology 159(1), 115-
121. doi: 10.1111/j.1476-5381.2009.00395.x
13
Yuill K. H., Borg J. J., Ridley J. M., Milnes J. T.,
Witchel H. J., Ashok A. P., Kozlowski R. Z., and Hancox
J. C.. (2004) Potent inhibition of human cardiac
potassium (hERG) channels by the anti-estrogen agent
clomiphene—without
QT
interval
prolongation
Biochemical and Biophysical Research Communications
318, 556–561. doi: 10.1016/j.bbrc.2004.04.063
14
Di Veroli, G.Y., Davies, M.R., Zhang, H., Abi-
Gerges, N., Boyett, M. R. (2014) hERG Inhibitors with
Similar Potency But Different Binding Kinetics Do Not
Pose the Same Proarrhythmic Risk: Implications for
Drug Safety Assessment, Journal of Cardiovascular
Electrophysiology 25(2). doi : 10.1111/jce.12289
15
Smith G. A., Rocha E. M., Rooney T., Barneoud P.,
McLean J. R., Beagan J., Osborn T., Coimbra M., Luo
Y., Hallett P. J., Isacson O., (2015) A Nurr1 Agonist
Causes Neuroprotection in a Parkinson’s Disease Lesion
Model Primed with the Toll-Like Receptor 3 dsRNA
Inflammatory Stimulant Poly(I:C), Plos One 1-14. doi :
10.1371/journal.pone.0121072
16
Loppi, S., Kolosowska, N. (2018) HX600, a synthetic
agonist for RXR-Nurr1 heterodimer complex, prevents
ischemia-induced neuronal damage, Brain, Behavior, and
Immunity 73, 670–681. doi: 10.1016/j.bbi.2018.07.021