Synthesis and in vitro biological evaluation of new pyrimidines as glucagon-like peptide-1 receptor agonists

Article abstract of DOI:10.1016/j.bmcl.2017.09.032

The therapeutic success of peptide glucagon-like peptide-1 (GLP-1) receptor agonists for the treatment of type 2 diabetes mellitus has inspired discovery efforts aimed at developing orally available small-molecule GLP-1 receptor agonists. In this study, two series of new pyrimidine derivatives were designed and synthesized using an efficient route, and were evaluated in terms of GLP-1 receptor agonist activity. In the first series, novel pyrimidines substituted at positions 2 and 4 with groups varying in size and electronic properties were synthesized in a good yield (78–90%). In the second series, the designed pyrimidine templates included both urea and Schiff base linkers, and these compounds were successfully produced with yields of 77–84%. In vitro experiments with cultured cells showed that compounds 3a and 10a (10^?15–10^?9 M) significantly increased insulin secretion compared to that of the control cells in both the absence and presence of 2.8 mM glucose; compound 8b only demonstrated significance in the absence of glucose. These findings represent a valuable starting point for the design and discovery of small-molecule GLP-1 receptor agonists that can be administered orally.

Full text of DOI:10.1016/j.bmcl.2017.09.032

Accepted Manuscript
Synthesis and in vitro biological evaluation of new pyrimidines as glucagon-
like peptide-1 receptor agonists
Shaikha S. AlNeyadi, Abdu Adem, Naheed Amer, Alaa A. Salem, Ibrahim M.
Abdou
PII:
S0960-894X(17)30928-9
DOI:
http://dx.doi.org/10.1016/j.bmcl.2017.09.032
BMCL 25296
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
18 June 2017
3 September 2017
13 September 2017
Please cite this article as: AlNeyadi, S.S., Adem, A., Amer, N., Salem, A.A., Abdou, I.M., Synthesis and in vitro
biological evaluation of new pyrimidines as glucagon-like peptide-1 receptor agonists, Bioorganic & Medicinal
Chemistry Letters (2017), doi: http://dx.doi.org/10.1016/j.bmcl.2017.09.032
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Synthesis and in vitro biological evaluation of new pyrimidines as
glucagon-like peptide-1 receptor agonists
Shaikha S. AlNeyadia, Abdu Ademb, Naheed Amerb, Alaa A. Salema and Ibrahim M. Abdou*a
aDepartment of Chemistry, College of Science, UAE University Al-Ain, 15551 UAE
bDepartment of Pharmacology, College of Health and Science, UAE University Al-Ain, 17666 UAE
Correspondence and requests for materials should be addressed to Ibrahim M. Abdou (email: i.abdou@uaeu.ac.ae)
ABSTRACT: The therapeutic success of peptide glucagon-like peptide-1 (GLP-1) receptor agonists for the treatment of type 2 diabetes mellitus has
inspired discovery efforts aimed at developing orally available small-molecule GLP-1 receptor agonists. In this study, two series of new pyrimidine
derivatives were designed and synthesized using an efficient route, and were evaluated in terms of GLP-1 receptor agonist activity. In the first series, novel
pyrimidines substituted at positions 2 and 4 with groups varying in size and electronic properties were synthesized in a good yield (78-90%). In the second
series, the designed pyrimidine templates included both urea and Schiff base linkers, and these compounds were successfully produced with yields of 77-
84%. In vitro experiments with cultured cells showed that compounds 3a and 10a (10-15 to 10-9 M) significantly increased insulin secretion compared to that
of the control cells in both the absence and presence of 2.8 mM glucose; compound 8b only demonstrated significance in the absence of glucose. These
findings represent a valuable starting point for the design and discovery of small-molecule GLP-1 receptor agonists that can be administered orally.
Keywords: type 2 diabetes, GLP-1, pyrimidine analog, insulin secretion
The cellular uptake of blood glucose due to the action of insulin secreted from the endocrine pancreas is
facilitated by gut hormones. The development of the incretin concept was based on the observation that enteral
1
nutrition provided a more potent insulinotropic stimulus than an intravenous challenge did. Glucose-dependent
2
insulinotropic polypeptide (GIP) was the first incretin to be discovered. GIP is a 42-amino acid hormone
synthesized in duodenal and jejunal enteroendocrine K cells in the proximal small bowel. A second incretin
hormone, glucagon-like peptide-1 (GLP-1), was identified later from proglucagon. GLP-1 is a 30-residue peptide
hormone released from intestinal L cells following nutrient consumption. It potentiates the glucose-induced
secretion of insulin from pancreatic β cells, increases insulin expression, inhibits beta-cell apoptosis, promotes
beta-cell neogenesis, reduces glucagon secretion, delays gastric emptying, promotes satiety, and increases
peripheral glucose disposal. These multiple effects have generated a great deal of interest in the discovery of
long-lasting agonists of the GLP-1 receptor (GLP-1R) in order to treat type 2 diabetes. Both GIP and GLP-1 exert
their actions by binding to distinct G-protein-coupled receptors (GPCRs). These receptors are members of the
class B/II family of seven transmembrane GPCRs. 3 Activation of both incretin receptors on β cells leads to rapid
increases in levels of cAMP and intracellular calcium, followed by insulin exocytosis, which occurs in a glucose-
dependent manner. 4
Whereas in healthy humans oral glucose elicits a considerably higher insulin secretory response than
does intravenous glucose, this incretin effect is substantially reduced or absent in patients with type 2 diabetes. 5
In type 2 diabetes mellitus, the homeostasis of postprandial glucose is impaired by the dysregulation of insulin
secretion and high glucagon levels. In addition, impairment of incretin results in reduced secretion of GLP-1 and
subsequent progression of pancreatic islet dysfunction. 6
Therefore, the development of incretin-based therapeutics may be an effective strategy to restore normal islet
function in type 2 diabetes. Since GLP-1 activity remains relatively preserved in diabetes patients, most
pharmaceutical efforts that are directed at potentiating the action of incretin to treat type 2 diabetes have focused
4-5, 7
on GLP-1R agonists. Recent reports have described activation of the GLP-1R by substituted quinoxalines
and a cyclobutane derivative 8, suggesting the possibility of developing nonpeptide GLP-1R agonists.

Abbreviations
GLP-1, glucagon-like peptide-1; GLP-1R, glucagon-like peptide-1 receptor; SEM, standard error of the mean; DMSO, dimethyl sulfoxide; NMR, nuclear
magnetic resonance; FT-IR, Fourier transform infrared (spectroscopy); DIPEA, N,N-diisopropyl ethylamine; GPCR, G-protein-coupled receptor; GIP,
glucose-dependent insulinotropic polypeptide
1

Considering the above, we report the development of novel, nonpeptide pyrimidine analogs as GLP-1R agonists.
These novel pyrimidines were synthesized and evaluated for their antidiabetic effects in comparison to those of
the potent drug, exenatide. These molecules may offer a therapeutic advantage because of their ability to act
alone or in combination with GLP-1. Pyrimidines compounds are likely to interacts with an allosteric site of the
GLP-1 receptor. A similar hypothesis was proposed previously for the quinoxaline series of GLP-1 receptor
agonists 9 and some reported antidiabetic pyrimidine-based compounds exert their agonistic effect on the GLP-1
receptor via an allosteric mechanism 10.
Our synthesis efforts focused on the development of a new template that can be used to generate novel
pyrimidines, substituted at C-2 and C-4 positions with groups varying in size, steric properties, and electronic
properties (Fig. 1).
Figure 1. Template of the designed disubstituted pyrimidines 3a-e
The synthetic routes to derivatives 3a-e were relatively fast and efficient, requiring two steps to achieve
the final products with a microwave heating protocol. In the first step, 2,4-dichloropyrimidine 1 was converted
into 2-chloro-4-substituted-pyrimidine 2 in the presence of N,N-diisopropylethylamine (DIPEA) in approximately
8 min using microwave irradiation (yield: 85-93%). In toluene, the 4-arylaminopyrimidine intermediates 2 were
then reacted with the second nucleophile using microwave irradiation for 10 min to produce the target products
3a-e in relatively good yield (78-90%) (Scheme 1).
Scheme 1. The synthetic route of compounds 3a-e. Reagents and conditions: (a) Ar-NH2, N,N-diisopropylethylamine
(DIPEA), ethanol, microwave, 100°C, 8 min; (b) Cyclic or aromatic amine, toluene, microwave, 80-100°C, 10 min.
The structures of the products 3a-e were confirmed based on their elemental and spectroscopic properties
1
(FT-IR, H- and 13C-NMR). The IR spectrum (KBr,, cm-1) of compound 3a showed a signal at υ = 3247 cm-1
representing (-NH). Another band appeared at υ = 3185 cm-1 corresponding to the C-H aromatic, while the C-H
1
aliphatic appeared at υ = 2926 cm-1. The H-NMR (400 MHz, DMSO-d6) spectrum of compound 3a showed a
multiplet at δ = 1.31-1.80 ppm, integrated for 12 protons and attributed to the corresponding cycloheptyl ring.
The benzyl protons resonated as a doublet at δ = 4.42 ppm with coupling constant J = 4.7 Hz. Another signal
appeared at δ = 5.68 ppm as a doublet, corresponding to the NH- proton exchanged with D2O. The pyrimidine H-
5 and H-6 appeared as two doublets at δ = 6.10 and 7.59 ppm, respectively, with equal coupling constants of J =
6.0 Hz. The 13C-NMR spectrum of compound 3a showed signals at δ = 24.4, 28.3, 34.9, 43.5, and 51.6 ppm that
were designated as the cycloheptyl carbons. The pyrimidine carbons C-2, C-6, C-4, and C-5 resonated at δ =
161.6, 155.6, 162.9, and 95.3 ppm, respectively (see supplementary data).
The formation of 3e was also confirmed using FT-IR spectroscopy, which revealed the appearance of
NH2 bands at υ = 3564 and 3357 cm-1. The C=N stretching appeared at υ = 1455 cm-1. Bands were assigned for –
1
SO2NH2 at υ = 1207 and 1160 cm-1. The H-NMR (400 MHz, DMSO-d6) spectrum of compound 3e showed a
broad signal at δ = 7.42 ppm, which was assigned to the NH2 protons exchanged with D2O. The phenyl protons
appeared at δ = 7.75-7.91 ppm, while the pyrimidine H-5 and H-6 resonated as two doublets at δ = 6.71 and 8.13
ppm, respectively, with equal coupling constants of J = 8.0 Hz. The pyrimidine carbons C-4, C-6, C-2, and C-5
2

appeared at δ = 153.1, 145.3, 161.1, and 100.1 ppm, respectively. The phenyl carbons resonated at δ = 121.9 and
127.0-127.2 ppm (see supplementary data).
An unsymmetrically substituted urea is a common structural feature of many biologically active
11
compounds, such as enzyme inhibitors and pseudopeptides. Sulfonylureas were found to have applications as
12
oral antidiabetic drugs and herbicides. However, urea derivatives can also be used as glycation protectors,
especially against advanced glycation end products. 13
Moreover, a series of unsymmetrical phenylurenyl chalcone derivatives were synthesized and evaluated
for in vitro antimalarial activity.14 Encouraged by these facts, the present investigation involves designing new
disubstituted pyrimidine templates with both urea and Schiff base linkers (Fig. 2).
Figure 2. Disubstituted pyrimidine template for compounds 8a-d
In the present study, the synthesis of disubstituted pyrimidines 8a-d started with intermediate 5, which
was obtained by the reaction of 2-amino-4-chloropyrimidine 4 with hydrazine hydrate. The resultant
hydrazopyrimidine 5 was reacted with p-fluoroaldehyde 6 in a Schiff condensation to form the 4-substituted 2-
aminopyrimidine 7 with a 95% yield. In the final step, isocyanate was allowed to react with compound 7 at room
temperature for 12 h under dry conditions to afford the target products 8a-d in 79-84% yields (Scheme 2).
Scheme 2. The synthesis of compounds 8a-d. Reagents and conditions: (a) NH2NH2.H2O, ethanol, reflux, 30 min; (b) p-
fluorobenzaldehyde, Ethanol, acetic acid, microwave, 15 min; (c) R-NCO, acetonitrile, 25°C, 12 h.
The formation of 8b was confirmed using FT-IR spectroscopy, which revealed the appearance of the urea
NH band at υ = 3442 cm-1, while the Schiff-base NH- appeared at υ = 3360 cm-1. The C=O stretching was
observed at υ = 1682 cm-1. The 1H-NMR (400 MHz, DMSO-d6) spectrum of compound 8b showed multiplets at
δ = 0.83-0.86 ppm, and δ = 1.25-1.34 ppm was assigned to the cyclopentyl ring protons. The phenyl protons
resonated at δ = 7.96-7.99 ppm, while the pyrimidine H-5 and H-6 resonated as two doublets at δ = 6.24 and 7.82
ppm, respectively, with equal coupling constants (J = 4.0 Hz). The olefinic proton appeared at δ = 8.24 ppm. The
NH proton of Schiff base appeared as a doublet at δ = 7.66 ppm, with a coupling constant J = 8.0 Hz exchanged
with D2O. The two NH protons of the urea linker resonated at δ = 8.35 ppm and δ = 8.58 ppm, exchanged with
D2O. The 13C-NMR spectrum showed that C-4, C-6, C-2, and C-5 of the pyrimidine ring resonated at δ = 167.4,
162.6, 152.8, and 99.8 ppm, respectively, the carbonyl group resonated at δ = 145.9 ppm, and δ = 116.2-130.3
ppm represented the aromatic carbons of the fluorobenzene (see supplementary data).
Compounds 10a,b were prepared by the reaction of 2,4-diaminopyrimidine 9 with isocyanate derivatives
to form the urea linker at position 4 of the pyrimidine ring with a yield of 77-83% (Scheme 3).
3

Scheme 3. The synthetic route of compounds 10a,b. Reagents and conditions: (a) R-NCO, acetonitrile, 25°C, 2-3 h.
The formation of 10b was confirmed using FT-IR spectroscopy, which revealed the two NH2 bands at υ
= 3506 and 3370 cm-1, while the NH group of the urea linker appeared at υ = 3170 cm-1. The C=O stretching
1
appeared at υ = 1700 cm-1. The H-NMR (400 MHz, DMSO-d6) spectrum of compound 10b showed that the
pyrimidine H-5 and H-6 resonate as two doublets at δ = 6.08 and 7.91 ppm, respectively, with equal coupling
constants (J = 6.0 Hz). The two NH groups in the urea linker resonated at δ = 9.48 and 11.77 ppm, exchanged
with D2O. The NH2 group of pyrimidine C-2 appeared at δ = 7.61 ppm, exchanged with D2O. The 13C-NMR
spectrum showed that pyrimidine C-4, C-6, C-2, and C-5 resonated at δ = 157.8, 155.2, 163.9, and 99.8 ppm,
respectively. The carbonyl group resonated at δ = 152.4 ppm, and signals appeared at δ = 119.8, 123.2, 129.2,
and 139.2 ppm that were assigned to the aromatic carbons of the phenyl substituent (see supplementary data).
Secretion of insulin by βTC6 cells was measured using the high-range insulin Sandwich ELISA kit
described in the experimental section (see supplementary data). Fig. 3 shows the glucose response of the βTC6
cells in the absence of drugs. Glucose at 2.8 mM induced a mild insulin secretion of approximately 3000 pmol/L,
which was used in subsequent testing of the novel pyrmidine analog compounds and the positive control,
exenatide. Exenatide treatment caused a significant increase in insulin secretion compared to basal secretion from
the βTC6 cells. Moreover, in the presence of 2.8 mM glucose, 10-12 and 10-5 M exenatide significantly increased
insulin secretion compared to that of controls (i.e., 2.88 mM glucose alone) (Fig. 4a).
The in vitro effects of compound 3a at 10-15, 10-12, and 10-9 M on insulin secretion in the absence and
presence of 2.8 mM glucose are shown in Fig. 4b. In the absence of glucose, 10-15 and 10-12, of compound 3a
significantly increased insulin secretion compared to that of the basal control. In the presence of 2.8 mM glucose,
10-15 M of 3a significantly increased insulin secretion compared to that of the control (i.e., with 2.8 mM glucose
alone, Fig. 4b). Regarding compound 8b, Fig. 4c shows that, in the absence of glucose, 10-15 and 10-12 M of
compound 8b significantly increased insulin secretion compared to that of the basal control, while compound 8b
had no significant effect on insulin secretion in the presence of 2.8 mM glucose (Fig. 4c). In the absence of
glucose, all tested concentrations of compound 10a significantly increased insulin secretion compared to that of
the basal control (Fig. 4d). In the presence of 2.8 mM glucose, insulin secretion with 10a treatment increased in a
concentration-dependent manner, but only 10-9 M compound 10a was statistically different from the control value
(i.e., with 2.8 mM glucose alone).
In this work, our compounds were evaluated as GLP-1R agonists. Compound 10a showed similar effects
as did exenatide in stimulating insulin secretion from βTC6 cells. The presence of the amino group at position 2
produced a significant increase in the magnitude of the response, suggesting that the hydrogen bond donor is
preferred in this region and affects binding to the ago-allosteric site of the GLP-1R. On the other hand,
replacement of the amino group at position 2 of the pyrimidine ring with other substitutes resulted in reduced
antidiabetic potential. It can be deduced that the presence of any group at the 2-position of the pyrimidine could
sterically hinder the interaction of the compound with its receptor.
***
10000
8000
***
6000
4000
2000
0
***
0
2.8
5.6
11.2
Glucose mM
Figure 3. The glucose response of the βTC6 cells in the absence of drugs. Plotted values are means of triplicates ± SEM*; P
< 0.05, ** P < 0.01, *** P < 0.001 versus 0 mM glucose.
4

Control
Control
a
b
-12
**
#
10-15
10-12
10
10E-15 M
14,000
12,000
10,000
8,000
6,000
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0
-9
10-12
10-9
10
10E-12 M
##
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1,800
1,600
1,400
1,200
1,000
800
*
-7
10-9
**
10-7
10
#
10E-9 M
**
-5
***
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10-5
**
10
**
*
***
*
600
400
200
0
Basal(no Glucose) + 3a Glucose (2.8 mM)
Stimulated + 3a
Basal Exenatide
Glucose stimulated
Exenatide
Control
Control
c
-15
d
10E-15 M
-15
10
10E-15 M
10
**
#
-12
10-12
10E-12 M
12,000
10
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*
-9
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10
10,000
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10E-9 M
*
*
**
**
*
*
*
Basal(no Glucose) + Glucose (2.8 mM)
10a Stimulated + 10a
Basal(no Glucose) + Glucose (2.8 mM)
8b Stimulated + 8b
Figure 4. The effects of exenatide (10-12 –10-5 M, panel a) and test compounds 3a (panel b), 8b (panel c), and 10a (panel
d)(10-15 –10-9 M) on insulin secretion in βTC6 cells in the absence (Basal, left bars) and in the presence of 2.8 mM glucose
concentration (right bars). Results are means of triplicates ± SEM; *P < 0.05, ** P < 0.01, *** P < 0.001 versus basal
control, and #P < 0.05, ## P < 0.01, ### P < 0.001 versus 2.8 mM glucose alone.
In summary, our results with the pyrimidine-based GLP-1R agonists in vitro demonstrate that modulating
glucose-dependent insulin secretion with low molecular weight compounds is technically feasible. A new series
of substituted pyrimidine analogs, 3a-d, 8a-d, and 10a-b, were synthesized using an economical and
environmentally friendly procedure. The anti-diabetes activities of the newly synthesised compounds were
evaluated in cultured cells. These results confirmed that compounds 3a, and 10a could significantly increase
insulin secretion compared to that of the control cells in the absence and presence of 2.8 mM glucose; compound
8b only demonstrated significance in the absence of glucose. Compound 10a was similar to exenatide regarding
insulin secretion from the βTC6 cells. Moreover, these findings provide pharmacological guidance for the
discovery and characterization of small-molecule GLP-1R ligands as possible therapeutics. However, further
work is needed to improve the potency and optimize the pharmacokinetic properties of these molecules to enable
clinical development. Future studies will focus on characterizing the allosteric binding site and the ligand-
mediated conformational changes that are induced by pyrimidine analogs to potentiate receptor signaling. A
better understanding of the pocket and mechanism of activation will facilitate molecular modeling strategies to
develop more potent small-molecule GLP-1R agonists.
Acknowledgements
This work was supported by the UAE University, Research Affairs Sector [grant no. 31S030-1156-02-02-10].
Supplementary data
Supplementary data associated with this article can be found, in the online version, at
https://1drv.ms/b/s!Aoxf511qpqQthgbZRPTfm4RqADK1
5

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7

**
#
12,000
10,000
8,000
6,000
4,000
2,000
0
*
Control
*
*
**
*
*
10-15 M
10-15
10-12
10-12 M
10-9
10-9 M
Basal(no Glucose) +
10a
Glucose (2.8 mM)
Stimulated + 10a
In vitro biological evaluation of pyrimidine 10a as glucagon-like peptide-1 receptor agonists
8