Development of novel liver?X?receptor modulators based on a 1,2,4-triazole scaffold

Article abstract of DOI:10.1016/j.bmcl.2018.12.025

Liver X Receptor (LXR) agonists have been reported as a potential treatment for atherosclerosis, Alzheimer's disease and hepatitis C virus (HCV) infection. We have designed and synthesized a series of potent compounds based on a 1,2,4-triazole scaffold as novel LXR modulators. In cell-based cotransfection assays these compounds generally functioned as LXR agonists and we observed compounds with selectivity towards LXRα (7-fold) and LXRβ (7-fold) in terms of potency. Assessment of the effects of selected compounds on LXR target gene expression in HepG2 cells revealed that compounds 6a-b and 8a-b behaved as inverse agonists on FASN expression even though they were agonists in the LXRα and LXRβ cotransfection assays. Interestingly, these compounds had no effect on the expression of SREBP-1c confirming a unique LXR modulator pharmacology. Molecular docking studies and evaluation of ADME properties in-silico show that active compounds possess favorable binding modes and ADME profiles. Thus, these compounds may be useful for in vivo characterization of LXR modulators with unique profiles and determination of their potential clinical utility.

Full text of DOI:10.1016/j.bmcl.2018.12.025

Accepted Manuscript
Development of novel liver X receptor modulators based on a 1,2,4-triazole
scaffold
Shaimaa S. Goher, Kristine Griffett, Lamees Hegazy, Mohamed Elagawany,
Mohamed M.H. Arief, Amer Avdagic, Subhashis Banerjee, Thomas P. Burris,
Bahaa Elgendy
PII:
S0960-894X(18)30970-3
https://doi.org/10.1016/j.bmcl.2018.12.025
BMCL 26194
DOI:
Reference:
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
26 September 2018
30 November 2018
12 December 2018
Please cite this article as: Goher, S.S., Griffett, K., Hegazy, L., Elagawany, M., Arief, M.M.H., Avdagic, A.,
Banerjee, S., Burris, T.P., Elgendy, B., Development of novel liver X receptor modulators based on a 1,2,4-triazole
scaffold, Bioorganic & Medicinal Chemistry Letters (2018), doi: https://doi.org/10.1016/j.bmcl.2018.12.025
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Development of novel liver X receptor
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modulators based on a 1,2,4-triazole scaffold
Shaimaa S. Goher, Kristine Griffett, Lamees Hegazy, Mohamed Elagawany, Mohamed M. H. Arief, Amer
Avdagic, Subhashis Banerjee, Thomas P. Burris, and Bahaa Elgendy
8
b
EC50 = 113 nM (LXRɑ), 231 nM (LXRβ)

Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com
Development of novel liver X receptor modulators based on a 1,2,4-triazole
scaffold
a
b
c
c
a
Shaimaa S. Goher , Kristine Griffett , Lamees Hegazy , Mohamed Elagawany , Mohamed M. H. Arief ,
b
c
b
a,b,
Amer Avdagic , Subhashis Banerjee , Thomas P. Burris , and Bahaa Elgendy
a
Chemistry Department, Faculty of Science, Benha University, Benha 13518, Egypt
b
Center for Clinical Pharmacology, Washington University School of Medicine and St. Louis College of Pharmacy, St. Louis, MO 63110, USA
Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA
c
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
Liver X Receptor (LXR) agonists have been reported as a potential treatment for atherosclerosis,
Alzheimer’s disease and hepatitis C virus (HCV) infection. We have designed and synthesized a
series of potent 1,2,4-triazole scaffolds as novel LXR modulators. In cell-based cotransfection
assays these compounds generally functioned as LXR agonists and we observed compounds with
selectivity towards LXR (7-fold) and LXR (7-fold) in terms of potency. Assessment of the
effects of selected compounds on LXR target gene expression in HepG2 cells revealed that
compounds 6a-b and 8a-b behaved as inverse agonists on FASN expression even though they
were agonists in the LXR and LXR cotransfection assays. Interestingly, these compounds had
no effect on the expression of SREBP-1c confirming a unique LXR modulator pharmacology.
Molecular docking studies and evaluation of ADME properties in-silico show that active
compounds possess favorable binding modes and ADME profiles. Thus, these compounds may
be useful for in vivo characterization of LXR modulators with unique profiles and determination
of their potential clinical utility.
Keywords:
Liver X receptor
Agonist
1
,2,4-Triazole
HCV
ADME
2
009 Elsevier Ltd. All rights reserved.
—
——

Corresponding author. Tel.: +1-314-446-8336; fax: +1-314-446-8136; e-mail: belgendy@wustl.edu

Liver X receptors (LXRs) have emerged as a promising drug
targets because they effectively regulate lipid metabolism and
inflammation. LXRs are known as oxysterol receptors and have
two isoforms, LXRα (NR1H3) and LXRβ (NR1H2). In humans,
LXRα consists of 447 amino acids and is expressed mainly in liver,
kidney, intestine, adipose tissue, and macrophages; LXRβ consists
of 460 amino acids and is expressed ubiquitously.1,2
OH
OH
O
F3C
F3C
O
O
S
N
O
Ph
F3C
N
Ph
CF3
Cl
T0901317
GW3965
A growing body of literature indicates that LXR is a potential
drug target for a range of diseases. LXR agonists have been shown
to increase reverse cholesterol transport and reduce atherosclerosis
by targeting induction of ATP-binding Cassette Transporter A1
1
2
2
-7
(
ABCA1) gene expression. Agonists have also been shown to
2
,8,9
4
N
have anti-inflammatory activity.
Efficacy in Alzheimer’s
3
disease models and cancer models has also been demonstrated for
N2
1
N
2
,8,,10-14
5
LXR agonists.
Stimulation of hepatic lipogenesis by
agonists (via stimulation of transcription of SREBP-1c, FASN,
and SCD1) has limited development of agonists for treatment of
these diseases.
3
Figure 1. LXR agonists 1-3.
This has led to efforts to develop LXR modulators that would
display tissue selective gene modulation effects (e.g. ABCA1) so
as to retain the ability to activate key beneficial pathways while
avoiding those that are detrimental (e.g. SREBP-1c). The potential
utility of LXR ligands has continued to expand. LXR agonists have
been shown to reduce the replication of hepatitis C virus via
targeting key genes that are required for HCV replication. Based
on the ability of LXR to regulate de novo lipogenesis, we have
evaluated LXR inverse agonists for their ability to suppress tumor
growth and to treat non-alcoholic steatohepatitis with success .14,16
We have synthesized a library of new LXR agonists based on
,2,4-triazole scaffold 3, which we divided into three parts as
1
highlighted in Figure 1. We studied the structure activity
relationships (SAR) by modifying these three parts, namely
substituents at N-1, C-3, and C-5 through different chemical
transformations. The structures of synthesized compounds were
elucidated using different spectroscopic techniques.
1
5
3,5-disubstituted-1H-1,2,4-triazoles (6a-l) were synthesized by
reacting nitriles (4a,b) with hydrazides (5a-l) in n-butanol in the
2
0
presence of anhydrous potassium carbonate at 150 ᵒC. The
synthesized triazoles (6a,d,e,g) reacted with different alkyl halides
in DMF to give 1-alkyl-3,5-disubstituted-1H-1,2,4-triazoles (7a-
Compound 3 is a new LXR modulator that was recently
identified using pharmacophore modeling and shape-based virtual
1
7
screening. When this compound was evaluated in an LXR
luciferase reporter gene assay, it showed moderate partial agonist
activity compared to LXR full agonist GW3965 (2). Development
of a partial agonist may be advantageous since LXR full agonists
have been demonstrated to cause severe adverse side effects due
to elevation of hepatic lipogenesis. There is no additional
structure-activity-relationship (SAR) data in the literature on
compound 3. The 1,2,4-triazole heterocycle is an important
building block for the synthesis of biologically active molecules
and found wide variety of applications in medicinal chemistry.18,19
2
1
l). Acetyl triazoles (8a-e) were obtained by refluxing 3,5-
disubstituted-1H-1,2,4-triazoles (6a,e,f,g,i) with acetic anhydride.
Sulphonyl derivatives (9a,b) were obtained via reacting 6a,g with
p-toluene sulfonyl chloride in presence of suitable base (Scheme
1
).
We evaluated the activity of synthesized compounds in a cell
based (HEK293 cells) cotransfection assay using either full-length
human LXRα or LXRβ and a reporter containing 3 copies of an
LXR response element (LXRE) within the promoter of a luciferase
reporter gene. We initially decided to evaluate the activity of 3,5-
disubstituted-1H-1,2,4-triazoles (6a-l) as the core scaffold of
ligand 3. Testing these compounds against both LXR isoforms
showed potent agonistic activity. The parent triazole 6a showed
potent agonist activity against LXRα (EC50 for LXRα = 142 nM)
and moderate activity against LXRβ (EC50 for LXRβ = 1008 nM).
Compound 6a was 7-fold selective for LXRα over LXRβ. Then,
As part of our ongoing research to discover novel LXR
modulators of clinical importance,14,16 we developed new LXR
agonists based on the 1,2,4-triazole scaffold 3 to evaluate them as
potential drugs.
we explored the effect of substituents on the phenyl ring at C-3
2
(
R ). Electron withdrawing substituents at 2-position of the phenyl
ring (6b and 6c) showed good agonistic activity against both LXR
isoforms, higher efficacy toward LXRβ, and slight selectivity
toward LXRα (Table 1). Switching the position of Cl and Br from
2
-position to 4-position (6d and 6e) enhanced the agonistic activity
against both LXR isoforms and reversed the selectivity toward
LXRβ (Table 1).

R2
N
R2
N
O
a
N
b
N
R1
N
NH2
+
R2
N
H
a-l
R1
N
R1
N
4
a-b
H
5
3
R
1
6a-l
4
a: R = Ph-
7a-l
1
4
b: R = Bn-
R2
R2
N
N
c
d
N
R1
N
6a,e,f,g,i
6a,g
N
R1
N
O S
O
O
8a-e
9a-b
3
Scheme 1. Reagents and conditions: (a) K
2
CO
3
, n-BuOH, 150 °C; (b) R Cl, K
2
CO
3
, DMF, reflux; (c) Ac
2
O, reflux 2-3 h; (d) TsCl, pyridine, reflux 6 h
Table 1. LXR activity of 1,2,4-triazole derivatives 6a-l
LXRα
LXRβ
Compound
R1
Ph-
Ph-
Ph-
Ph-
Ph-
Ph-
R2
Ph-
EC50 (nM)
142
526
390
309
164
77
E
max (%)
EC50 (nM)
1008
640
493
245
68
85
68
ia
6152
ia
E
63
max (%)
EC50 ɑ/β
0.14
0.82
0.79
1.26
2.41
0.91
1.59
-
0.36
-
0.59
-
ClogP
3.40
3.57
3.63
3.64
3.73
3.50
3.24
2.32
3.54
3.52
3.87
3.99
6
6
6
6
6
6
6
6
6
6
6
6
a
b
c
d
e
f
56
60
52
51
55
62
60
-
45
-
46
-
2-Cl-Ph-
2-Br-Ph-
4-Cl-Ph-
4-Br-Ph-
4-CH
3-CH
74
67
60
62
73
72
-
59
-
61
73
3
-Ph-
g
h
i
j
k
l
Ph-
Ph-
Ph-
PhCH
PhCH
PhCH
3
O-Ph-
3-Pyridyl
108
ia
2202
ia
570
ia
PhCH
Ph-
2
-
2
2
2
-
-
-
2-Cl-Ph-
4-Cl-Ph-
966
2573
ia = inactive at 10 μM
a
E
max (%) is the percentage ratio between maximum fold induction of the tested compound and fold induction for 1 at 10 μM.
2
Electron donating groups on the phenyl ring of R enhanced the
agonistic activity against both LXR isoforms significantly.
Compound 6f with CH group at 4-position was potent dual
3
disrupt their π-π stacking with the surrounding aromatic residues.
For example, compound 6b was predicted to make π-π stacking
with Phe271, Phe340, Phe329 and a halogen bond with Thr316 but
agonist for LXRα (EC50 for LXRα = 77 nM) and LXRβ (EC50 for
LXRβ = 85 nM). Similarly, compound 6g was potent dual agonist
2
the change in geometry in 6k due to the extra CH , led to flipping
of the binding pose and loss of the halogen bond interaction and
(EC50 = 108 and 68 nM, for LXRα and LXRβ, respectively), but
one of the π-π stacking interactions (Figure S1). Similarly, if we
more selective toward LXRβ by 1.6-fold. Compound 6g was
docked in the LBP of LXRβ (Figure 2A). The ligand makes mainly
hydrophobic contacts with Ile309, Met312, Leu313, Ile327,
Phe329 and Leu274. The tautomer of compound 6g makes
hydrogen bonding interaction through the hydrogen atom on N-1
to Thr271. Methoxy group made another hydrogen bond with
Thr316, which is likely responsible for higher potency of
compound 6g over compound 6a that lacks hydrogen-bond donor
at this position.
compare 6d to 6l, the addition of CH
complementarity of the ligand within the binding pocket where
CH group was displaced out of the hydrophobic region and
2
linker led to less
2
located instead in a hydrophilic region (Figure S2). Therefore, we
1
suggest that aromatic substitution at C-5 (R ) is important to
maintain good agonistic activity.
Next, we investigated the effect of substituting N-1 with different
1
alkyl groups while maintaining R as a phenyl group and changing
2
the substituent pattern at R by synthesizing compounds 7a-l
When we replaced the phenyl group in 6a with 3-pyridyl group
in 6h, the compound lost the agonistic activity against both
isoforms. Interestingly, the clogP of this compound is the lowest
in this series and this might be the reason for the loss of activity.
Replacing the phenyl group in 6a with benzyl group in 6i reduced
the agonistic activity for both LXR isoforms but showed ≈ 2.8-fold
selectivity toward LXRα (Table 1).
(
Table 2). Alkylating compound 6a with different alkyl groups
provided compounds 7a-e. Substituting N-1 with methyl group in
a reduced the agonistic activity dramatically toward LXRα (≈7-
7
fold) and slightly toward LXRβ (≈ 2.6-fold) if compared to the
parent triazole 6a. Compounds 7b-e with an ethyl, butyl, ally, and
benzyl groups at N-1 were very weak agonists against LXRα and
completely inactive against LXRβ (Table 2). Compound 7f where
1
2
3
Changing substituents at C-5 (R ) from phenyl group (6a) to
R is 3-methoxy phenyl and R is benzyl group showed moderate
agonistic activity against LXRα (EC50 for LXRα = 903 nM), and
weak activity against LXRβ (EC50 for LXRβ = 2365 nM). This
compound was ≈ 2.6-fold more selective toward LXRα over
LXRβ. On the contrary, the corresponding analogue, 6g, was more
selective toward LXRβ over LXRα by ≈ 1.6-fold. Comparison of
the docking poses of compounds 6g and 7f in the LBP of LXRβ
predicts that adding alkyl groups at the N-1 position disrupted the
ligand’s complementarity in the ligand binding pocket leading to
flipped binding pose for compound 7f and loss of both hydrogen
bonds formed by compound 6g tautomer with amino acid residues
Thr316 and Phe271 (Figure 2B).
benzyl group (6j), diminished the agonistic activity toward both
LXRα and LXRβ. Substituting the phenyl group at C-3 of 6j with
chlorine in 2-position (6k) regained the agonistic activity toward
LXRα (EC50 = 570 nM) and LXRβ (EC50 = 966 nM). Transposition
of chlorine atom to 4-position (6l) rendered the compound inactive
against LXRα and lowered the activity toward LXRβ by ≈ 4.9-fold
compared to 6j and by ≈ 2.7-fold compared to 6k. Addition of CH
as a linker between the triazole ring and the phenyl ring at C-5 in
j, 6k, and 6l caused the geometry to be tilted in all three
2
6
compounds if compared to their corresponding derivatives, 6a, 6b,
and 6d. This change in the geometry might affect the
complementarity of 6j, 6k, and 6l within the binding site and

Table 2. LXR activity of 1,2,4-triazole derivatives 7a-l
LXRα
LXRβ
Comp.
R1
R2
R3
CH
EC50 (nM)
2468
ia
E
64
-
65
-
58
62
77
60
-
53
45
78
max (%)
EC50 (nM)
2637
ia
ia
ia
E
71
-
-
-
max (%)
EC50 ɑ/β
0.94
-
-
-
-
0.38
0.60
-
ClogP
3.69
4.92
5.08
4.56
5.40
3.24
4.22
4.64
5.58
6.17
4.79
6.24
7
7
7
7
7
7
7
7
7
7
7
7
a
b
c
d
e
f
Ph-
Ph-
Ph-
Ph-
Ph-
Ph-
Ph-
Ph-
Ph-
Ph-
Ph-
Ph-
Ph-
Ph-
Ph-
Ph-
Ph-
3-CH
3
-
C
C
C
2
4
3
H
H
H
5
9
5
-
-
-
2470
ia
PhCH
PhCH
2
2
-
-
2178
903
ia
-
3
O-Ph-
2365
1985
ia
69
83
-
g
h
i
j
k
l
4-Cl-Ph-
4-Cl-Ph-
4-Cl-Ph-
4-Cl-Ph-
4-Br-Ph-
4-Br-Ph-
CH
3
-
1189
2285
ia
2130
2237
5025
C
C
2
H
H
5
-
4
9
-
ia
-
-
PhCH
C H -
2 5
PhCH
2
2
-
-
6706
5647
712
61
71
69
0.32
0.40
7.06
ia = inactive at 10 μM
a
E
max (%) is the percentage ratio between maximum fold induction of the tested compound and fold induction for 1 at 10 μM.
A. B.
Figure 2. A. Molecular interactions of compound 6g in the LBP of LXRβ. B. Overlay of compounds 6g tautomer (green) and 7f (pink). Hydrogen bonds are
shown in blue dotted lines.
Alkylation of 6d and 6e with different alkyl groups afforded
compound 7g-l. These compounds showed similar pattern to their
corresponding analogues 7a-f, where they showed weak activity
against both LXR isoforms. Compound 7l showed good activity
toward LXRβ (EC50 for LXRβ = 712 nM) and was 7-fold more
selective to LXRβ over LXRα (Table 2). This compound was the
most lipophilic among synthesized compounds (clogP = 6.24) and
it was shown by Ishikawa that higher lipophilicity is important for
contacts with surrounding residues such as Phe271, Ile327,
Phe329, Leu313, Met312, Ile309, and Phe349 (Figure 3).
Acetylation of 6f led to 8c, which exhibited 3- and 4-fold lower
activity against LXRα and LXRβ, respectively. Compound 8d
showed good agonistic activity against both LXR isoforms. There
was no real difference in agonistic activity between 6g and 8d
toward LXRα, while there was a change in EC50 from 68 nM in 6g
to 109 nM in 8d. This difference was compensated slightly by
increase in Emax from 72% in 6g to 78% in 8d. Compound 8e
showed more than 3- and 4-fold enhancement in agonistic activity
over the parent 6i toward LXRα and LXRβ, respectively. Similar
to the parent 6i, compound 8e is 2-fold more selective toward
LXRα over LXRβ.
2
2
LXRβ selectivity. It is noteworthy that the ligand binding pockets
for both LXRα and LXRβ are very similar. Therefore,
rationalizing ligand selectivity to both receptors based on ligands’
interactions only is not possible and other aspects of molecular
recognition such as receptor-ligand dynamics and entropy should
1
1
be taken into consideration. Molecular dynamics simulations and
free energy calculations are currently underway to determine the
molecular basis of differential selectivity between LXRα and
LXRβ.
We next explored the effect of acylating parent triazoles 6a, 6e,
6
f, 6g, and 6i using acetic anhydride to form acetyl derivatives 8a-
e. Substituting N-1 with acetyl group in 8a lowered the agonistic
activity toward LXRα by 2.8-fold, but increased the agonistic
activity and selectivity toward LXRβ significantly (EC50 for LXRβ
=
232 nM, EC50 ɑ/β = 1.71) if compared to the parent triazole 6a.
Compound 8b showed a higher agonistic activity toward LXRα
and slight increase in Emax (58% for 8b vs 55% for 6e) if compared
to 6e (Table 1 and Table 3). The agonistic activity of 8b toward
LXRβ was significantly lower than 6e but Emax increased from
6
2% to 78% (Table 1 and Table 3). Compound 8b was 2-fold more
selective for LXRα. Docking of compound 8b in the LBP of LXRβ
predicts that this compound is stabilized by forming a hydrogen
bond with Thr316 and with van der Waals forces and hydrophobic
Figure 3. Molecular interactions of compound 8b in the LBP of LXRβ.
Hydrogen bonds are shown as blue dotted lines and π-π stacking interactions
are shown as dotted red lines.

Finally, we explored the possibility of substituting N-1 with
tosyl group by synthesizing 9a and 9b. Compound 9a was > 4- and
unexpectedly decreased FASN expression even though they
behaved as agonists in both LXR and LXR cotransfection
assays. SREBP-1c is another gene that is involved in lipogenesis
and T0901317 (1) increased expression of this gene almost 9-fold
(Table 4). Compounds 6a-b and 8a-b that acted as agonists in the
cotransfection assays and inverse agonists in terms of FASN
expression had no effect on expression of the well characterized
LXR target gene SREBP-1c. These data suggest that the 1,2,4-
triazole compounds are a novel class of LXR modulators that
display context dependent agonism/inverse agonism.
1
8
8
2-fold less active against LXRα than the corresponding 6a and
a, respectively. On the other hand, 9a possess similar activity to
a against LXRβ and 3.9-fold higher activity than 6a against the
same isoform. Compound 9b was completely inactive against both
LXRα and LXRβ. We did not explore scaffold 9 further because it
is not stable for long time at room temperature and tend to
decompose to the parent triazole.
The SAR of synthesized compounds revealed that 3,5-
disubstituted 1,2,4-triazoles are generally good modulators of
LXR when the two substituents are phenyl rings or substituted
phenyl rings (e.g. 6a-6g). Substituting the phenyl ring at C-3 of the
triazole ring with electron withdrawing groups make the
compounds behave as dual agonists toward both LXR isoforms
with slight selectivity toward LXRβ (e.g. 6b-6e). Electron
donating substituents at the same ring increased the potency
toward both LXR isoforms significantly (e.g. 6f and 6g).
Substituting C-3 of the triazole ring with pyridine renders the
compound inactive (e.g. 6h). Similarly, the compounds lost
activity when C-5 was substituted with benzyl group (e.g. 6j-6l).
Substituting N-1 of the triazole ring with different alkyl groups led
to mostly inactive compounds (e.g. 7a-7l). On the other hand,
substituting N-1 with acetyl group gave compounds of comparable
potency to the parent triazole with higher efficacy (e.g. 8a-8d).
We calculated a set of physical descriptors and pharmaceutical
2
3
properties of the selected compounds using Qikprop to predict
their absorption, distribution, metabolism, and excretion (ADME)
properties (Table 5). All compounds comply with Lipniski’s rule
2
4
25
of five and Jorgensen’s rule of three and are predicted to have
good oral bioavailability and excellent absorption through cell
membranes.
In conclusion, we have developed novel and potent LXR
modulators based on 1,2,4-triazole scaffolds. Several of our new
agonists exhibit good isoform selectivity in a cell based
cotransfection assay where they generally behave as agonists.
Interestingly,
these
compounds
display
“modulator”
pharmacology since they function as inverse agonists in terms of
FASN expression and are inactive on SREBP-1c expression in
contrast to the activity observed in cotransfection assays. These
new modulators possess excellent ADME properties and can be
developed further to examine their unique modulator properties in
vivo.
We measured the effect of T0901317 (1), 6a-b, and 8a-b on
gene expression of direct target genes of LXR: Fatty acid synthase
(FAS), Sterol Regulatory Element Binding Protein 1c (SREBP-
1
c), 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR), and
LXRɑ. LXR agonists increase the expression of LXR target genes
FASN and SREBP-1c in the liver causing increased de novo
lipogenesis. Long term effects of increased expression of these
genes can lead to hepatosteatosis, severe inflammation, and liver
damage. We utilized the liver HepG2 immortalized cell line as a
model to examine the effects of LXR ligands on these two genes.
While we observed very efficacious agonist activity for T0901317
Acknowledgments
Bahaa Elgendy thanks the Science and Technology
Development Fund (Egypt) for financial support (STDF-STF
Grant 11969).
(1) in terms of induction of FASN, compounds 6a-b and 8a-b
Table 3. LXR activity of 1,2,4-triazole derivatives 8a-e and 9a-b
LXRα
EC50 (nM)
LXRβ
Comp.
R1
R2
R3
E
max (%)
EC50 (nM)
232
231
351
109
1425
259
ia
E
max (%)
EC50 ɑ/β
1.71
0.49
0.65
1.06
0.49
6.58
-
ClogP
2.84
3.43
3.15
2.91
3.20
3.66
3.73
8
8
8
8
8
9
9
a
b
c
d
e
Ph-
Ph-
Ph-
Ph-
Ph-
Ph-
Ph-
Ph-
4-Br-Ph-
4-CH
3-CH
PhCH
Ph-
CH
CH
CH
CH
CH
3
3
3
3
3
CO-
CO-
CO-
CO-
CO-
396
113
228
115
701
1705
ia
56
58
53
62
50
75
-
63
78
62
78
68
81
-
3
-Ph-
O-Ph-
3
2
-
a
b
4-CH
4-CH
3
-C
-C
6
6
H
H
4
-SO
-SO
2
2
-
-
3-CH
3
O-Ph-
3
4
ia = inactive at 10 μM
a
E
max (%) is the percentage ratio between maximum fold induction of the tested compound and fold induction for 1 at 10 μM.
Table 4. Normalized mRNA expression of FASN and SREBP-1c with 6a-b, 8a-b.
Gene
Compound
Normalized mRNA Expression
SEM (+/-)
T0901317 (1)
2.6210
0.7264
0.6393
0.6517
0.4448
8.950
0.988
0.865
0.890
0.893
0.630
0.156
0.390
0.075
0.091
0.215
0.190
0.157
0.091
0.715
6
6
8
8
a
b
a
b
FASN
T0901317 (1)
6
6
8
8
a
b
a
b
SREBP-1c
Table 5. Calculated Molecular Descriptors for Prediction of ADME properties for selected compounds. Recommended values or range
for 95% of known drugs is shown in parenthesis.
a
b
c
d
e% Human Oral fPSA
Absorption
gQplogS
hQPPCaco
i#metab
(2 -8)
jQplogBB
(-3 – 1.2)
kQPPMDCK
Comp.
mol_MW
QPlogPo/w
-2 – 6)
HBD
(0 – 6)
HBA
(

(
7
130 –
25)
(2-
20)
(<25 % Low, >
80% High)
(7 –
200)
(-6.5 -
.0.5)
(< 25 Poor,
> 500
(< 25 Poor, >
500
Excellent)
2905.99
2897.74
2973.15
2973.84
3028.45
Excellent)
1567.17
1562.36
1606.355
4258.532
1638.673
6
6
8
8
8
a
g
a
b
d
221.26
251.29
263.298
342.194
293.324
3.4
1
1
0
0
0
2.5
3.25
5
5
5.7
100
100
100
100
100
39.2
47.5
53.2
53.1
61.1
-4.012
-4.27
-3.81
-4.69
-3.654
0
1
0
0
1
0.059
-0.016
0.042
0.216
-0.024
3.24
2.84
3.428
2.9
a
b
c
Molar weight in Daltons; Logarithm of partitioning coefficient between n-octanol and water phases (range for 95% of drugs: -2 to 6); Estimated number of
hydrogen bonds that would be donated by the solute to water molecules in an aqueous solution. Values are averages taken over a number of configurations, so they
can be non-integer.; d Estimated number of hydrogen bonds that would be accepted by the solute from water molecules in an aqueous solution.Values are averages
e
taken over a number of configurations, so they can be non-integer; Predicted human oral absorption on a 0 -100 % scale, based on a multiple linear regression
f
g
–3 h
model; Polar surface area; Predicted aqueous solubility, log S. S in mol dm ; Predicted apparent Caco-2 cell permeability in nm/sec as a model for the gut-blood
i
j
k
barrier. Number of possible metabolic reactions; Predicted brain/blood partition coefficient; Predicted apparent MDCK cell permeability in nm/sec as a mimic
for blood/ brain barrier. Qikrop predictions are for non-active transport.
1
1
6. Griffett K, Solt LA, El-Gendy B.-E. M, Kamenecka TM, Burris
TP. ACS Chem Biol. 2013;8(3):559-567.
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2014;54(2):367-371.
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Supplementary Material
2
Supplementary material that may be helpful in the review
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file. That file can then be transformed into PDF format and
submitted along with the manuscript and graphic files to the
appropriate editorial office.
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