Synthesis, in vitro ADME profiling and in vivo pharmacological evaluation of novel glycogen phosphorylase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2020.127117

A small set of indole-2-carboxamide derivatives identified from a high-throughput screening campaign has been described as a novel, potent, and glucose-sensitive inhibitors of glycogen phosphorylase a (GPa). Among this series of compounds, compound 2 exhibited moderate GP inhibitory activity (IC₅₀ = 0.29 μM), good cellular efficacy (IC₅₀ = 3.24 μM for HepG2 cells and IC₅₀ = 7.15 μM for isolated rat hepatocytes), together with good absorption, distribution, metabolism, and elimination (ADME) profiles. The in vivo animal study revealed that compound 2 significantly inhibited an increase of fasting blood glucose level in adrenaline-induced diabetic mice.

Full text of DOI:10.1016/j.bmcl.2020.127117

Journal Pre-proofs
Synthesis, in vitro ADME profiling and in vivo Pharmacological Evaluation
of Novel Glycogen Phosphorylase Inhibitors
Guang-xin Miao, You-de Wang, Zhi-wei Yan, Li-ying Zhang
PII:
S0960-894X(20)30206-7
DOI:
Reference:
https://doi.org/10.1016/j.bmcl.2020.127117
BMCL 127117
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
26 September 2019
14 February 2020
17 March 2020
Please cite this article as: Miao, G-x., Wang, Y-d., Yan, Z-w., Zhang, L-y., Synthesis, in vitro ADME profiling
and in vivo Pharmacological Evaluation of Novel Glycogen Phosphorylase Inhibitors, Bioorganic & Medicinal
Chemistry Letters (2020), doi: https://doi.org/10.1016/j.bmcl.2020.127117
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Graphical Abstract
Synthesis, in vitro ADME profiling, and in
vivo Pharmacological Evaluation of Novel
Glycogen Phosphorylase Inhibitors
Leave this area blank for abstract info.
Guang-xin Miao, You-de Wang, Zhi-wei Yan, and Li-ying Zhang
Ph
O
O
Cl
HN
Cl
NH
O
N
N
N
O O
H
N
OH
H
OR
H
1
2
R=CH3
R=H
CP-91149
N
NH
Cl
HN
NH2
Cl
HN
N
OH
N
O
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com
1
2
Synthesis, in vitro ADME profiling and in vivo Pharmacological Evaluation of
Novel Glycogen Phosphorylase Inhibitors
3
Guang-xin Miao, You-de Wang, Zhi-wei Yan, and Li-ying Zhang 
4
5
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Key Laboratory of Traditional Chinese Medicine Research and Development of Hebei Province, Institute of Traditional Chinese Medicine, Chengde Medical
University, Chengde 067000, China
—
——
ARTICLE INFO
ABSTRACT

Corresponding author. Tel.: +86-314-229-1000; e-mail: zzzhangliying@126.com
Article history:
Received
Revised
Accepted
Available online
A small set of indole-2-carboxamide derivatives identified from a high-throughput screening
campaign has been described as a novel, potent, and glucose-sensitive inhibitors of glycogen
phosphorylase a (GPa). Among this series of compounds, compound 2 exhibited moderate GP
inhibitory activity (IC50 =0.29 μM), good cellular efficacy (IC50= 3.24 μM for HepG2 cells and
IC50 = 7.15 μM for isolated rat hepatocytes), together with good absorption, distribution,
metabolism, and elimination (ADME) profiles. The in vivo animal study revealed that compound
Keywords:
Diabetes
Glycogen phosphorylase inhibitors
Biological activity
ADME
2
significantly inhibited an increase of fasting blood glucose level in adrenaline-induced diabetic
mice.
2
020 Elsevier Ltd. All rights reserved.
Blood glucose
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0
1
2
With the improvement of people's living standard, diabetes mellitus has gradually become the third major disease endangering
human health. In adults, type 2 diabetes accounts for approximately 90-95% of all diagnosed cases of diabetes, and develops most often
among middle-aged and older adults. Inhibition of glycogen phosphorylase (GP) has been regarded as a therapeutic strategy for blood
1
1
1
1
glucose control in diabetes, and various studies have shown the efficacy of GP inhibitors in lowering blood glucose in animal models of
2
,3
diabetes and in clinical trials.
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1
1
1
1
1
3
4
5
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In the literature, there are several examples of small-molecule allosteric inhibitors of this enzyme, most of them are derived from a
4
high-throughput screening. As this class of molecules contains an indole-2-carboxamide moiety, as exemplified by CP-91149 (Fig. 1),
5
the binding site is termed the indole site (PDB code 1pyg). CP-91149 inhibits human liver GP with an IC50=110 nM in the presence of
6
7.5 mM glucose, and was 5-10 times less potent in the absence of glucose. Thus, it can be concluded that with low concentration of
glucose, the inhibitory activity of these molecules is certainly lower than that with high glucose concentration. It is a significant
advantage against the risk of hypoglycemia in patients with type 2 diabetes.
1
2
2
2
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0
1
2
Since CP-91149 has poor water solubility (<1 mg/mL) and consequently low bioavaility, there are a lot of analogues have developed
Herein, we report the discovery, synthesis, and biological evaluation of a small set of compounds prepared from a high-throughput
screening in order to find more potent GP inhibitors with good pharmacokinetic properties. Moreover, in vitro DMPK studies and in
vivo pharmacological evaluation are also presented.
2
2
3
4
Figure 1. Structures of CP-91149 and the target compounds 1-4.
2

2
2
2
2
5
6
7
8
The synthesis of compound 1-2 is summarized in Scheme 1. Treatment of Boc-L-phenylalanine with glycine methyl ester
hydrochloride in the presence of EDCI in anhydrous DMF at room temperature afforded dipeptide ester 6. Removal of the protected
group from 6 with TFA furnished intermediate 7, which was reacted with 5-chloroindole-2-carboxylic acid through the action of T
and DIEA to obtain compound 1. Hydrolysis of 1 with LiOH provided carboxylic acid derivative 2.
3
P
2
9
3
3
0
1
Scheme 1. Reagents and conditions: (a) Glycine methyl ester hydrochloride, EDCI, HOBT, DMAP, DIEA, r.t., 63%; (b) TFA, CH
carboxylic acid, T P, DIEA, CH Cl , 0 C to r.t., 34%; (d) LiOH, THF, reflux, 52%.
2 2
Cl , r.t.; (c) 5-chloroindole-2-
3
2
2
3
3
3
3
3
2
3
4
5
6
As shown in Scheme 2, compound 3 was obtained in a similar manner starting from Boc-D-phenylalanine. In the presence of the
condensation agent EDCI, Boc-D-phenylalanine 8 interacts with ammonium hydroxide to afford the corresponding amide 9. Cleavage
of the protecting group of 9 with 2 N HCl afforded hydrochloride salt 10. Direct coupling of 10 with Boc-glycine through the action of
EDCI and DIEA yielded compound 11. Subsequent deprotection of compound 11 using TFA gave compound 12, which was reacted
with 5-chloroindole-2-carboxylic acid using the condensation agent EDCI to afford target compound 3.
3
7
3
3
8
9
Scheme 2. Reagents and conditions: (a) ammonium hydroxide (28% in water), EDCI, HOBT, THF, r.t., 46%; (b) 2 N HCl(aq), r.t., 73%; (c) Boc-glycine, EDCI,
2 2
HOBT, DIEA, DMF, r.t., 63%; (d) TFA, CH Cl , r.t., 85%; (e) 5-chloroindole-2-carboxylic acid, EDCI, HOBT, DIEA, 0 C to r.t., 45%.
4
4
4
4
4
0
1
2
3
4
We also synthesized the weak hydrophilic benzimidazole derivative 4 by the method shown in Scheme 3. Reaction of L-tyrosine
with (Boc) O produced intermediate 14. Direct coupling of 14 with o-phenylenediamine dihydrochloride in the presence of HATU and
DIEA afforded the expected amide derivative 15. Subsequently, in the presence of acetic acid, cyclization of amide 15 was completed
via aldol reaction to obtain benzimidazole derivative 16. Finally, amidation of 16 with 5-chloroindole-2-carboxylicacid yielded target
compound 4.
2
4
5
4
4
6
7
2
Scheme 3. Reagents and conditions: (a) (Boc) O, triethylamine, 50% 1,4-dioxane/water, 0 °C to 80 °C, 91%; (b) o-phenylenediamine dihydrochloride, HATU,
DIEA, DMF, r.t. to 45 °C, 50%; (c) acetic acid, 60 °C, 59%; (d) 5-chloroindole-2-carboxylic acid, HATU, DIEA, DMF, r.t. to 45 °C, 50%.
4
4
5
5
5
5
5
8
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0
1
2
3
4
The above synthesized derivatives were evaluated in an enzyme inhibition assay against rabbit muscle glycogen phosphorylase a
7
(RMGPa) (Table 1) according to previous literature reports. As described previously, the activity of rabbit muscle GPa was measured
6
by detecting the release of phosphate from glucose-1-phoaphate in the direction of glycogen synthesis. All the synthesized compounds
showed good inhibitory activity. Among the compounds, dipeptide ester 1 (IC50 = 0.05 μM) showed the most efficient inhibition with a
lower IC50 value than that of the positive control CP-91149 (IC50 = 0.0922 μM). Derivative 2 with a free carboxylic function and
derivative 3 with a weak hydrophilic benzimidazole group diminished inhibitory potency than the CP-91149. This may be due to the
lipid/water partition coefficient and the group flexibility.
5
5
To evaluate the effects of all compounds in cells, glycogenolysis assays were conducted in both rat and human liver cells based on a
3

6
5
5
5
5
6
6
7
8
9
0
published method. The results are summarized in Table 1. It is not surprising that the compounds retained their micromolar inhibitory
activities. Interestingly, their inhibitory activities in both HepG2 cells and isolated rat hepatocytes showed a very similar trend with
their activities in the GP inhibition assay. Among the compounds, compound 1 showed the best activity in HepG2 cells and isolated rat
hepatocytes, with IC50 values of 0.67 μM and 0.72 μM, respectively. It was 5-fold more potent than the positive control CP-91149 in
HepG2 cells and 4-fold more potent than CP-91149 in rat hepatocytes cells.
6
6
6
6
1
2
3
4
The effect of varying glucose concentration on the IC50 values of both compounds 1 and 2 is shown in Fig. 2. The data were
normalized by dividing the IC50 obtained at different glucose concentrations by the IC50 observed in the absence of glucose. At high
glucose concentrations, the relative IC50 values of both compounds 1 and 2 were decreased by 2- to 5-fold, respectively. Therefore,
glucose had the same relative effect on the IC50 of both compounds 1 and 2.
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6
6
6
6
7
7
5
6
7
8
9
0
1
In order to explore molecular mechanism of action, compound 1 and 4 were docked into the binding site of human liver glycogen
phosphorylase A (Fig. 3). The docking score values reflected the differences between their bioactivity (Table 1). These two compounds
shared common protein-ligand interactions, including the hydrogen bonds generated with Arg60 and Glu190. However, because of their
chirality, different orientations were taken by the two compounds. Additional two hydrogen bonds with Thr38’ and Arg60’
strengthened the protein-ligand interactions between compound a and the binding site. But for compound 4, only one hydrogen bond
with Tyr185’ was found. Therefore, the differences of bioactivity between compound 1 and 4 could be attributed to the protein-ligand
interactions caused by the chirality.
7
2
Table 1. Bioactivity assay for compounds 1-4 and Glide Docking Score of compounds 1, 4.
a
a
a
IC50 (nM,
IC50 (nM,
IC50 (nM, rat
Glide Docking
Score
Compound
RMGPa)
HepG2 cells)
hepatocytes)
4
8.7±4.2
661.5±82.4
719.5±79.5
-9.114
ND c
1
2
3
2
89.4±1.5
3238.9±703.0
6472.9±327.7
8391.8±5706.5
3310.4±257.5
7150.0±2421.6
7650.0±1320.0
9460.0±2035.9
3172.5±105.4
5
5
55.2±24.0
78.3±18.3
92.2±8.8
ND c
-8.683
4
CP-91149 b
a
b
c
7
7
7
3
4
5
Each value represents the mean ± SEM of three determinations.
CP-91149 was used as a positive control.
ND is not detected.
7
6
7
7
7
8
Figure 2. Effect of glucose on the potency of compounds 1-2. Their IC50 values for GPa inhibition were determined at varying glucose concentrations, and then
normalized by dividing the values by the IC50 value obtained in the absence of glucose. The normalized results are plotted as a function of glucose concentration.
7
8
9
0
Figure 3. Binding mode of compound 1 (Figure 3a) and 4 (Figure 3b) in the active site of human liver glycogen phosphorylase A (PDB ID: 1EXV).
8
8
8
8
8
1
2
3
4
5
Kinetic solubility and LogD values are important factors at the discovery stage that provide a rank listing of solubility values with
minimal sample requirements. Therefore, the solubility of three selected compounds was assessed using a high-throughput kinetic
solubility assay. As shown in Table 2, all the tested compounds showed comparable kinetic solubility. Of these, carboxylic acid
derivative 2 (187.82 µM) was slightly less soluble than the reference drug chloramphenicol (199.74 µM) at pH 7.4. However, the
initially made ester derivative 1 had low solubility and the best lipophilicities (log D7.4: 3.95), suggesting that it might easily pass the
8
4

8
8
6
7
phospholipid bilayer and to be absorbed, whereas 1 was distinctly more active (GP inhibitor with an IC50 value of 0.05 μM) than the
other two compounds. Compound 2, carrying a carboxylic acid group, had very low lipophilicity among this sub-group.
8
8
Table 2. In vitro physicochemical properties of compounds 1-3.
Kinetic
Solubility
log D7.4
(Oct/buff) result
Compound
Compound
pH=7.4 (µM)
1
2
3
1.89
187.82
36.84
1
2
3
3.95
0.72
3.32
Amiodarone
Chlorpromazi
ne (PC)
Propranolol
(PC)
<
1.00
3.23
1.38
(PC)
Chlorampheni
col (PC)
199.74
8
9
9
0
Three selected compounds were tested for their chemical and metabolic stability in multiple biological media, including simulated
gastric fluid (SGF), simulated interstinal fluid (SIF), mouse plasma (PLS), and mouse liver microsome (MLM).
9
9
9
9
1
2
3
4
As shown in Fig. 4, compound 2 exhibited considerable stability in all the media. It was stable in SGF and PLS for 24 h with almost
no detectable fragment. It was also stable in SIF for up to 1 h, but degraded within 6 h. Compound 1 is an unstable compound, which
was degraded completely within 1 h in SIF, 0.5 h in PLS, and 24 h by almost 50% in SGF. Moreover, compound 3 was a complicated
compound, which was relatively stable in SGF and PLS after 24 h of incubation, but degraded rapidly in SIF within 1 h.
9
5
9
9
9
9
6
7
8
9
Figure 34. Time-course of stability of compounds 1-3 (n = 3). (a) in SGF; (b) in SIF; (c) in mouse plasma.
Additionally, the compounds’ stability in microsome was evaluated by measuring the rate of compound consumption in MLM, and
the results are shown in Table 3. Compounds 2 and 3 showed good metabolic stability in MLM with longer half life (t1/2 > 145 min) and
slower elimination rate (CLint < 9.6 μL/min/mg protein, CL < 38.0 μL/min/mg protein). Compound 1 showed poor metabolic stability
with t1/2 of 15.4 min and CLint of 90 μL/min/mg protein.
1
00
1
01
Table 3. MLM stability of compounds 1-3.
Mouse liver microsomes
Sample
Name
T
min)
1/2
CLint
(μl/min/mg)
CL
R2
(
(mL/min/Kg)
1
2
0.9780
0.9419
0.9247
15.4
>145
>145
90.0
<9.6
<9.6
356.4
<38.0
<38.0
3
Diclofenac
0
.9827
27.1
51.2
202.8
(PC)
2
1
1
1
1
1
1
1
1
1
1
02
03
04
05
06
07
08
09
10
11
R is the correlation coefficient of the linear regression for the determination of kinetic constant.
CL = CLint • 45 mg microsome/g liver • g liver wt/kg body weight
Liver wt: 88 g/kg relative mouse liver weight
Based on their values in the biological assays and in vitro ADME profiling, compound 2 was evaluated for its hypoglycemic
activity in adrenaline-induced diabetic mice. Adrenaline is well known to induce high blood glucose level by indirectly stimulating
9
glycogenolysis and therefore increasing hepatic glucose production. Metformin was chosen as a positive control. Not surprisingly,
the preliminary animal study results (Fig. 5) showed that compound 2 significantly inhibited an increase in the fasted plasma glucose
level of diabetic mice induced by adrenaline. It reduced blood glucose (BG) level to a nadir of 446.25±15.9 mg/dl at 1.5 h vs
486.15±22.65 mg/dl in the vehicle-treated mice (p < 0.05), with significant effects also being evident at 1.5 h (p < 0.05). Further in
vivo studies on 2 and related products as hypoglycemic agents are ongoing.
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Table 4. Effect of compound 2 on fasted plasma glucose of hyperglycemic mice induced by adrenaline
5

Fasted plasma glucose (OD) (Mean±SEM)
AUC (0 min to 90
min, mg/dL× min)
Group
Dose (mg/kg)
0min
30min
60min
90min
Vehicle
4.84±0.15
4.76±0.15
4.86±0.16
4.85±0.16
4.89±0.16
9.58±0.44
8.85±0.58
9.03±0.26
9.52±0.45
8.92±0.27
8.41±0.48
7.56±0.49
482.63±21.01
373.73±19.78***
416.33±13.59*
451.13±20.43
449.03±15.53
Metformin
200
50
5.79±0.35*** 5.00±0.31***
2
2
2
6.83±0.38*
7.62±0.44
7.40±0.45
6.05±0.30*
6.70±0.35
7.47±0.50
25
12.5
a
b
c
1
1
1
1
13
14
15
16
Data are expressed as mean ± SEM (n = 10).
Metformin was used as a positive control.
*p < 0.05 and ***p < 0.005 vs vehicle.
1
17
1
1
18
19
Figure 45. Time-course of the glucose level-lowering effect of oral administration of compound 2 in diabetic mice induced by adrenaline. (n = 10; *p < 0.05 and
***p < 0.005 vs vehicle).
1
1
1
1
1
20
21
22
23
24
In the process of drug development and clinical application evaluation, the ADME property of compounds is one of the important
1
0, 11
indicators of drug-forming. Therefore, according to previous literature reports,
pharmacokinetic parameters the four target
compounds were predicted by Molinspiration online property calculation toolkit (http://www.molinspiration.com/). All compounds
meet requirements of Lipinski’s rule of five and shows good characterizing drug absorption range from 68.61% to 76.89%. This
provides a theoretical basis for further research.
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Table 5. The predicted ADME through Molinspiration online software.
MW c
n(rotb) d
(< 10)
8
miLogP e
(< 5)
n(ON) f
(< 10)
7
n(OHNH) g Lipinski’s
%ABS a
MV b
Compound
(
< 500)
413.86
399.83
398.85
430.89
(< 5)
violation
7
7
6
7
4.40
0.60
8.61
6.89
355.70
338.17
341.44
367.23
3.01
3
4
5
4
0
0
0
0
1
2
3
4
7
7
5
1.48
2.94
4.75
7
7
6
a
Percentage of absorption (%ABS); b Molecular volume (MV); c Molecular weight (MW); d Number of rotatable bonds (n-rotb); e Logarithm of partition
1
1
26
27
f
g
coefficient between n-octanol and water (miLogP); Number of hydrogen bond acceptors (nON); Number of hydrogen bond donors (nOHNH).
1
1
1
1
28
29
30
31
In summary, four novel indole-2-carboxamide derivatives were successfully identified from high-throughput screening as novel,
potent, and glucose-sensitive inhibitors of GPa. Biological evaluation of the synthesized compounds has been described. Our data
showed that compound 2 can inhibit glycogenolysis and then lower plasma glucose levels in diabetic rodents. The potency and ADME
values rendered this series worthy of continued exploration and development.
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Acknowledgments
1
1
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This work was supported by the National Natural Science Foundation of China (No. 81473101 and 81001401), the Natural Science
Foundation of Hebei Province (No. H2017406049), and the Key Program of Education Department of Hebei Province (No.
ZD2018080).
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Supplementary data
Supplementary data associated with this article can be found, in the online version, at…
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Conflicts of Interest: The authors declare no conflict of interest.
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Synthesis, in vitro ADME profiling, and in
vivo Pharmacological Evaluation of Novel
Glycogen Phosphorylase Inhibitors
Leave this area blank for abstract info.
Guang-xin Miao, You-de Wang, Zhi-wei Yan, and Li-ying Zhang
Ph
O
O
Cl
HN
Cl
NH
O
N
N
N
O O
H
N
H
OH
OR
H
1
2
R=CH3
R=H
CP-91149
N
NH
Cl
HN
NH2
Cl
HN
N
OH
N
O O
H
O
N
O
H
H
3
4
1
79
7