Design, Synthesis, and Structure-Activity Relationship Study of Pyrazolones as Potent Inhibitors of Pancreatic Lipase

Article abstract of DOI:10.1002/cmdc.202000850

Pancreatic lipase (PL), a key target for the prevention and treatment of obesity, plays crucial roles in the hydrolysis and absorption of in dietary fat. In this study, a series of pyrazolones was synthesized, and their inhibitory effects against PL were

Full text of DOI:10.1002/cmdc.202000850

Communications
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Design, Synthesis, and Structure-Activity Relationship
Study of Pyrazolones as Potent Inhibitors of Pancreatic
Lipase
Jing Zhang+,[b] Yang Yang+,[a] Xing-Kai Qian,[b] Pei-Fang Song,[b] Yi-Shu Zhao,[b]
Xiao-Qing Guan,*[b] Li-Wei Zou,*[b] Xiaoze Bao,*[a] and Hong Wang[a]
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prevention and treatment of obesity have become global task.
Numerous methods are available for the prevention and treat-
ment of obesity before serious clinical consequences become
apparent, such as lifestyle changes and drug intervention.[11]
Among these, pharmacotherapy is considered to be the most
commonly used one for the treatment of obesity.
Pancreatic lipase (PL), a key target for the prevention and
treatment of obesity, plays crucial roles in the hydrolysis and
absorption of in dietary fat. In this study, a series of pyrazolones
was synthesized, and their inhibitory effects against PL were
assayed by using 4-methylumbelliferyl oleate (4-MUO) as optical
substrate for PL. Comprehensive structure–activity relationship
analysis of these pyrazolones led us to design and synthesize a
novel compound P32 (5-(naphthalen-2-yl)-2-phenyl-4-(thio-
Pancreatic lipase (triacylglycerol acyl hydrolase, PL,E.C.
3.1.1.3), one of the most important serine hydrolases distributed
in the gastrointestinal tract, catalyzes the hydrolysis of the ester
bond of triacylglycerols to monoacylglycerols and fatty acids,
and plays a key role in dietary triacylglycerol absorption
(hydrolysis of 50–70% of total dietary fats).[12,13] The inhibition of
PL could restrain the hydrolysis of dietary glycerides of fat, and
thus reduce the subsequent intestinal absorption of the lipolysis
products (free fatty acids and monoacylglycerols). Therefore, PL
has become a promising target for the treatment of obesity.[14]
The first PL inhibitor orlistat (tetrahydrolipstatin) had been
approved by the Food and Drug Administration (FDA) for the
treatment of obesity in 1999.[15] At present, orlistat remains the
only PL inhibitor approved by FDA for obesity management in
conjunction with a reduced caloric diet. However, orlistat can
cause non-negligible adverse effects, including stomach pain,
steatorrhea and incontinence, abdominal cramping and fat-
soluble vitamin deficiencies, hepatotoxicity, and acute
pancreatitis.[16,17] Thus, it is highly desirable to find more safe
and effective PL inhibitors for the prevention and treatment of
obesity.
Pyrazolone, which was reported more than one century
ago, is a privileged five-membered nitrogen-containing phar-
macophore in medicinal chemistry as its derivatives possessing
many important biological properties.[18] The very first synthetic
antipyretic and analgesic drug phenazone was synthesized in
1883.[19] In recent years, many efforts have been devoted to
develop pyrazolone based lead compounds and drugs, such as
neuroprotective drug edaravone, antibacterial reagent, antitu-
mor reagent, p38 inhibitors, and our previously developed hCE1
inhibitor, and so on (Scheme 1).[20–22] In continue with our
interest in the development of lead compounds with pyrazo-
lone scaffold, the design of novel pancreatic lipase inhibitor
featuring this simple and easily accessible scaffolds will be a
promising candidate to overcome some of the side-effect of
orlistat. Herein, a series of easily accessible pyrazolones (P1–31)
were synthesized by a tow-step protocol and the inhibitory
effects of these compounds on PL were determined by using 4-
methylumbelliferyl oleate (4-MUO) as substrate probe. Compre-
hensive structure-activity relationship study brought novel
phen-2-ylmethyl)-2,4-dihydro-3H-pyrazol-3-one) as
a potent
mixed-competitive inhibitor of PL (IC50 =0.30 μM). In addition,
P32 displayed some selectivity over other known serine hydro-
lases. A molecular docking study for P32 demonstrated that the
inhibitory activity of P32 towards PL could be attributed to the
π-π interactions of 2-naphthyl unit (R1) and hydrophobic
interactions of phenyl moiety (R3) with the active site of PL.
Thus, P32 could serve as promising lead compound for the
development of more efficacious and selective pyrazolones-
type PL inhibitors for biomedical applications.
Obesity is a multifactorial disease defined as a long-term energy
in take over consumption, resulting in excessive energy stored
in the body in the form of fat (adipose tissue).[1] Being obese
increases the risk of many diseases and health conditions,
including type 2 diabetes,[2] coronary heart disease (CHD),[3]
dyslipidemia,[4] hypertension,[5] nonalcoholic fatty liver,[6,7] sleep
apnea.[8,9] As rates of obesity have soared over the past two
decades, it is increasingly clear that the number of people who
cannot achieve and maintain a healthy weight is not limited to
adults, but also includes children.[10] Obesity has become a
critical public health issue that is currently affecting billions of
people worldwide, especially children and adolescents. Hence,
[a] Y. Yang,+ Dr. X. Bao, Prof. H. Wang
College of Pharmaceutical Science & Collaborative Innovation Center of
Yangtze River Delta Region Green Pharmaceuticals
Zhejiang University of Technology
Hangzhou, 310014 (P. R. China)
E-mail: baoxiaoze@zjut.edu.cn
[b] J. Zhang,+ X.-K. Qian, P.-F. Song, Y.-S. Zhao, Dr. X.-Q. Guan, Prof. L.-W. Zou
Institute of Interdisciplinary Integrative Medicine Research
Shanghai University of Traditional Chinese Medicine
Shanghai, 201203 (P. R. China)
E-mail: chemzlw@shutcm.edu.cn
guanxq@shutcm.edu.cn
[+] These authors contributed equally to this work
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/cmdc.202000850
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Scheme 1. Examples of pyrazolone-based biological active compounds and the newly designed PL inhibitor.
Scheme 2. Synthesis of pyrazolones P1–31.
insights into the structure modification. A new 4-mono-
substituted pyrazolone P32 was designed and developed as a
powerful pancreatic lipase inhibitor (Scheme 1).
Our experiments were conducted with the preparation of a
series of variously substituted pyrazolones (P1–31) by a two-
step protocol (Scheme 2). Mono-alkylation of β-keto esters 1
with alkenyl halide in the presence of NaH in THF afforded the
mono-substituted β-keto esters 2 in quantitative yield. The
izations of compounds P11–P24 with the variation of R2 unit
demonstrated that compound P22 with the 2-thiopheny
substitute is more beneficial for compound inhibitory property
toward PL with IC50 value of 2.1 μM. Compound P27 with 2-
naphthyl unit (R1) afforded increased inhibitory effect against PL
compared with compound P10, while the variation of the
phenyl group (R3) with and alkyl group (P30 and P31) finally
resulted in a loss of potency. Comprehensive SAR analysis of all
tested pyrazolones (P1–P31) provide insights into the relation-
ships linking between the inhibitory effects on PL and the
substituent properties of these compounds. The 2-naphthyl unit
(R1), 2-thienyl (R2), and phenyl (R3) moieties were beneficial for
pyrazolones inhibitory property toward PL, and led to a
dramatic increase of the inhibitory effect on PL (Scheme 3).
°
following reaction with substituted hydrazine at 120 C gave
the corresponding pyrazolone P1–31 (see the Supporting
Information for more details).
Thirty-one pyrazolones (P1–P31) were assayed for their
inhibitory effects against PL. As shown in Table 1 (entries 1–31),
pyrazolone P1 with methyl (R1), benzyl (R2) and phenyl (R3)
substitutes demonstrated poor inhibitory effects on PL. Then,
we focused our attention on the variation of the R2 moiety of
pyrazolones (P2–P8). The phenyl unit (R2) of pyrazolone with
bromine substitute at the 4-position (P2) also displayed poor
inhibition toward PL with IC50 value of 95 μM, but the phenyl
unit with 4-chlorine (P3) and 4-methoxyl (P4) group showed
good inhibitory effect against PL with IC50 values of 23 and
15 μM, respectively. Compound P5 and P6, containing 2-
nitrophenyl and 2-methylphenyl unit, respectively, demon-
strated moderate inhibitory effects on PL, while the variation of
the phenyl group with 2-furanyl (P7) or 2-thienyl group (P8) led
to an increase of the inhibitory effects on PL. Compound P9
with ethyl substitute (R1) displayed stronger inhibition toward
PL than compound P1 (R1, methyl), while the variation of the
ethyl unit with phenyl unit compound P10 finally resulted in a
significant increase of potency (IC50, 10 μM). Further character-
Scheme 3. The structure–activity relationships and design of the novel
potent inhibitor.
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Table 1. The IC50 values of pyrazolones toward PL.[a]
1
2
P
R1
R2
R3
IC50 (PL) [μM]
3
4
5
6
7
8
9
1
2
3
4
5
6
7
8
P1
P2
P3
P4
P5
P6
P7
P8
Me
Me
Me
Me
Me
Me
Me
Me
Et
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Cy
Ph
>100
4-Br-C6H4
4-Cl-C6H4
4-OMe-C6H4
2-NO2-C6H4
2-Me-C6H4
2-furanyl
2-thienyl
Ph
95�15
23�2.7
15�4.2
45�11
63�12
16�2.6
9.4�1.6
57�5.0
10�1.9
7.6�2.0
19�3.5
11�1.5
4.0�0.4
14�1.8
9.1�1.0
8.9�1.2
9.4�1.5
9.0�0.8
22�2.9
3.9�0.40
2.1�0.32
32�3.5
22�3.6
2.2�0.36
1.0�0.13
0.71�0.055
13�1.4
11�2.7
>100
9
P9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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29
30
31
32
33
34
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37
38
39
40
41
42
43
44
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46
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50
51
52
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57
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
P10
P11
P12
P13
P14
P15
P16
P17
P18
P19
P20
P21
P22
P23
P24
P25
P26
P27
P28
P29
P30
P31
P32
orlistat[b]
Ph
4-Me-C6H4
3-Me-C6H4
2-Me-C6H4
4-OMe-C6H4
4-F-C6H4
2-Cl-C6H4
4-Br-C6H4
4-CF3-C6H4
3,5-(CF3)2-C6H3
2-NO2-C6H4
1-naphthyl
2-thienyl
Et
CHCH2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-Me-C6H4
3-Me-C6H4
2-naphthyl
2-F-C6H4
2-thienyl
Ph
Ph
12�2.5
0.30�0.050
0.19�0.045
2-naphthyl
2-thienyl
[a] All experimental data are averages of at least three independent experiments. [b] A positive inhibitor of PL.
Guided by these SAR results, we next designed and
synthesized a new 4-mono-substituted pyrazolone P32 that
might exhibit a more potent inhibitory effect on PL (Scheme 3).
The synthetic route is described in Scheme 4. Gratifyingly,
pyrazolones P32 was prepared from the methyl 3-(naphthalen-
2-yl)-3-oxopropanoate according a three-step procedure to
harvest the target compound. The novel pyrazolone P32
showed unusually potent inhibitory activity against PL with
much lower IC50 value of 0.30 μM (Table 1, entry 32). For
comparison, the known drug orlistat was tested under identical
conditions as a positive control (entry 33). The result indicated
that compound P32 showed similar inhibitory effect compared
with orlistat.
In order to further prove the specificity of compound P32
on PL, the selectivity of P32 inhibitory effect was then carried
out by a panel of most known serine hydrolase including
human carboxylesterase 1 (hCES1A), human carboxylesterase 2
(hCES2A), dipeptidyl peptidase IV (DPP-IV), butyrylcholinester-
ase (BChE) and thrombin according to the known assays.[23–28]
As shown in Table 2, compound P32 was found with lower
inhibitory effect on hCES1 A (IC50, 0.77 μM) and hCES2 A (IC50,
6.3 μM) compared with PL (IC50, 0.30 μM), and a poor inhibitory
effect on BChE, DPP-IV and thrombin with IC50 values greater
than 100. These results indicate that compound P32 is a good
inhibitor of PL with some selectivity over other serine hydro-
lases.
The strong inhibition potency of compound P32 against PL
encouraged us to further investigate the inhibition types and
the inhibition constants (Ki) of this compound toward PL, which
would facilitate to deeply understand the interactions between
P32 and PL. As shown in Figure 1, the inhibitory behavior of
P32 against PL-mediated 4-MUO hydrolysis was performed. The
dose-dependent inhibition curve demonstrated that P32 potent
inhibitory activity against PL. When the P32 concentration is
greater than 5 μM, the residual activity of PL is less than 20%. In
addition, the double reciprocal of Lineweaver-Burk plot clearly
demonstrated that a family of straight lines were intersected at
the first quadrant of the x,y-plane. Thus, compound P32 could
Scheme 4. Synthesis of pyrazolone P32. a) 2-Thenaldehyde, pyrrolidine
(10 mol%), AcOH (10 mol%), toluene, reflux; b) NaBH4, pyridine, RT; c)
PhNHNH2, 120 C.
°
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Table 2. IC50 values of compound P32 towards serine hydrolases.[a]
Oγ is 3.2 Å. however, there is no obvious interaction between
non-covalently inhibitor P32 and catalytic residue Ser153.[30]
These observations were highly consistent with the structure-PL
inhibition relationship studies above, as well as explained why
compound P32 exhibited the most potent PL inhibition activity
in a mixed-inhibition manner against PL-mediated 4-MUO
hydrolysis.
1
2
3
4
5
Serine hydrolase
IC50 [μM]
1
2
3
4
5
6
PL
0.30�0.050
0.77�0.066
6.3�1.0
>100
>100
>100
hCES1A
hCES2A
BChE
DPP-IV
thrombin
6
7
In summary, a novel pancreatic lipase (PL) inhibitor P32
based on pyrazolone scaffold featuring 2-naphthyl (R1), 2-
thienyl (R2), and phenyl (R3) substituents was developed
through a comprehensive structure-activity relationship analy-
sis. The pyrazolone P32, a mixed-competitive inhibitor, showed
strong activity to inhibit PL (IC50 0.30 μM) and displayed some
selectivity over other known serine hydrolase (hCES1A, hCES2A,
DPP-IV, BChE and thrombin). In addition, a molecular docking
study demonstrated that the π-π interactions of 2-naphthyl unit
(R1) and hydrophobic interactions of phenyl moiety (R3) with the
active site of PL should be responsible for the potent inhibitory
activity of P32 towards PL. This novel and promising lead
compound could enhance the development of pyrazolone-type
PL inhibitors for the prevention and treatment of obesity.
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[a] All experimental data are averages of at least three independent
experiments.
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Figure 1. Inhibition behaviors of P32 against PL mediated 4-MUO hydrolysis.
Left: the dose-dependent inhibition curve. Right: the Lineweaver–Burk plot.
All data represent the mean of triplicate determinations.
Acknowledgements
inhibit PL in a mixed-inhibition manner, with the Ki value of
0.77 μM.[29] We could infer from the results that the inhibitor
P32 may be not directly bind the hydrolysis active site (Ser153)
of the PL to against the hydrolysis of substrate 4-MUO.
To explore the interactions between P32 and PL at the
atomic level, molecular docking was carried out. As depicted in
Figure 2A, compound P32 could be well-docked into the
hydrophobic catalytic cavity of PL. As shown in Figure 2B, the 2-
Authors are grateful for the support of Zhejiang University of
Technology (2019414820029), the National Science and Technol-
ogy Major Project of China (2018ZX09731016-004), and the
National Key Research and Development Program of China
(2017YFC1702000).
naphthyl ring of P32 could create π-π interactions with Phe78, Conflict of Interest
Phe216, and Tyr115 of PL, suggesting that the 2-naphthyl unit
(R1) was important for PL inhibition. Meanwhile, we also found
that a phenyl (R3) moiety could form hydrophobic interactions
with Arg257, Val260, Ala261, and Leu265, thus suggesting that
the phenyl ring was also beneficial for PL inhibition. In addition,
the docking of compound P32 and 4-MUO with the active site
of PL (Figure S2) showed that the distance between the ester
linkages of the substrate 4-MUO and catalytic residue Ser153
The authors declare no conflict of interest.
Keywords: inhibitors
· pancreatic lipases · pyrazolones ·
structure-activity relationships
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Manuscript received: October 28, 2020
Revised manuscript received: January 30, 2021
Accepted manuscript online: February 2, 2021
Version of record online: ■■■, ■■■■
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J. Zhang, Y. Yang, X.-K. Qian, P.-F.
Song, Y.-S. Zhao, Dr. X.-Q. Guan*,
Prof. L.-W. Zou*, Dr. X. Bao*, Prof. H.
Wang
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Design, Synthesis, and Structure-
Activity Relationship Study of Pyr-
azolones as Potent Inhibitors of
Pancreatic Lipase
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Weighty matters: A new, potent,
promising lead compound for the de-
velopment of more efficacious and
selective pyrazolones-type PL inhibi-
tors for the prevention and treatment
of obesity.
mixed-competitive pancreatic lipase
(PL) inhibitor P32 has been developed
after comprehensive structure-activity
relationship analysis. It could serve as