Ureidopyridazine derivatives as acyl-CoA:cholesterol acyltransferase inhibitors

Article abstract of DOI:10.3797/scipharm.2006.74.85

A series of N-(2,4-difluorophenyl)-N′-heptyl-N′-{4- [(substituted)-pyridazin-3-yl)thio]pentyl}urea derivatives having a phenyl ring at positions 5 and/or at position 6 of the heterocycle, as well as the corresponding sulfones, were synthesized. Their inhi

Full text of DOI:10.3797/scipharm.2006.74.85

Scientia Pharmaceutica (Sci. Pharm.) 74, 85-97 (2006)
© Österreichische Apotheker-Verlagsgesellschaft m. b. H., Wien, Printed in Austria
85
Ureidopyridazine Derivatives as Acyl-CoA:cholesterol
acyltransferase Inhibitors
Arianna Gelain 1, Ilaria Bettinelli 1, Daniela Barlocco * 1, Byoung-Mog Kwon 2,
Tae-Sook Jeong 2, Kyung-Ran Im 2, Laura Legnani 3, Lucio Toma * 3
1 Istituto di Chimica Farmaceutica e Tossicologica, Università di Milano, Viale
Abruzzi 42, 20131 Milano, Italy
2 Korea Research Institute of Bioscience & Biotechnology, 52 Uen-Dong Yusung-
Ku, Taejeon 305-600, Korea
3 Dipartimento di Chimica Organica, Università di Pavia, Via Taramelli 10, 27100
Pavia, Italy
Abstract
A series of N-(2,4-difluorophenyl)-N’-heptyl-N’-^ 4-[(substituted)-pyridazin-3-
yl)thio]pentyl` urea derivatives having a phenyl ring at positions 5 and/or at position
6 of the heterocycle, as well as the corresponding sulfones, were synthesized.
Their inhibitory activity against acyl-CoA:cholesterol acyltransferase (ACAT) was
tested on the enzyme prepared from rat liver microsomes. Theoretical studies were
performed to correlate their activity to their structural features.
Keywords
Hypercholesterolemia, ACAT inhibitors, pyridazine derivatives, ureido
derivatives
Introduction
Hypercholesterolemia has been identified as one of the major risk factors for
coronary heart diseases. Many efforts have been directed towards the discovery of
new and effective hypocholesterolemic drugs [1, 2]. Acyl-CoA: cholesterol

86
Arianna Gelain et al.:
acyltransferase (ACAT) is a microsomial enzyme that catalyzes the formation of
long chain fatty acid cholesterol esters [3, 4, 5]. It represents an attractive target to
design novel hypolipidemic and anti-atherosclerotic drugs. Its inhibition produces a
reduction in intestinal absorption of cholesterol, liver secretion of very low-density
lipoprotein (VLDL) particles, and reduced accumulation of cholesteryl esters in the
arterial wall cells, the latter being a key step in the atherosclerotic process [6].
In previous papers [7-11] we reported our results on the design, the synthetic
approach, the enzyme inhibition assay, and the conformational study of several
mono- and diphenylpyridazine derivatives as novel ACAT inhibitors, including a
series of compounds [11], structurally related to the potent ureido derivative DuP
128 [12], in which a linear pentamethylene chain links the pyridazine moiety to a
substituted ureido group.
We have now undertaken a SAR study on the linker, in order to get information on
the essential requirements of this moiety for activity. As a first approach, branching
of the linker was considered. This paper reports on the synthesis and ACAT
inhibition activity of compounds 1a-c and 2a-c. In addition, attempts to correlate
their activity to their structural features through theoretical calculations are
presented.
Results and Discussion
All compounds were tested for their inhibitory properties towards ACAT extracted
from rat liver microsomes. Their activity, expressed as inhibition percentage at 50
Pg/ml, is shown in Table 1. Amongst the thioderivatives, the 5-phenyl derivative
(1b) showed the best activity with an inhibition percentage of 78. Both the 5,6-
diphenyl (1a) and the 6-phenyl derivative (1c) were weaker inhibitors (67% and
62%, respectively). Oxidation of 1b to its corresponding sulfone (2b) led to a
significant loss of potency. In the case of 1c, the same transformation did not bring
about any significant change (2c inhibition value was 64%). By contrast, oxidation

Ureidopyridazine Derivatives as Acyl-CoA: cholesterol acyltransferase Inhibitors
87
of 1a to the corresponding sulfone 2a, led to a compound provided with much
higher inhibitory activity (78%).
Scheme 1. Synthetic pathway to compounds 1a-c, 2a-c.
OH
O
H3C
O
a
NH(CH2)6CH3
b
+
CH3(CH2)6NH2
H3C
O
3
(CH2)6CH3
OH
OH
NH(CH2)6CH3
N
c
d
NH
H3C
H3C
O
F
4
5
F
R2
R1
N
N
(CH2)6CH3
Br
(CH2)6CH3
S
N
e
f
NH
H3C
N
NH
F
H3C
O
F
6
F
O
1a-c
F
R2
R1
N
N
O
(CH2)6CH3
S
a
b
c
R1 = R2 = Ph
R1 = Ph, R2 = H
R1 = H, R2 = Ph
O
N
NH
F
H3C
O
2a-c
F
a) PhCH3, N2, 18h, reflux; b) LiAlH4, THF, N2, 18h, reflux;
OCN
F
c)
e)
, CH2Cl2, N2, 1h, 0 °C; d) CBr4, P(Ph)3, CH2Cl2, 3h, rt;
F
N N
R2
SH
(7a-c), K2CO3, DMF, 6h, 80°C; f) Oxone, CH3OH, 4h, rt.
R1

88
Arianna Gelain et al.:
Tab. 1. Chemical data and rat ACAT inhibition of compounds 1a-c and 2a-c and
GERI-BP001M.
R2
R1
N
N
(CH2 ) 6 CH3
X
N
NH
F
H3 C
O
F
Compd
R1
R2
X
% Yield Formulaa
% Inhibition
at 50 Pg/mL
1a
Ph
Ph
H
Ph
H
S
52b
80b
40b
42c
22c
23c
C35H40F2N4OS
C29H36F2N4OS
C29H36F2N4OS
C35H40F2N4O3S
C29H36F2N4O3S
C29H36F2N4O3S
67
1b
S
78
62
78
66
64
83
1c
Ph
Ph
H
S
2a
Ph
Ph
H
SO2
SO2
SO2
2b
2c
Ph
GERI-BP001M
a) In vitro % ACAT inhibition determined in rat liver microsomes. All values are
means from three experiments, which differ by less than 10%. b) From 7a-c. c)
From 1a-c.
A modeling study of compounds 1a-c and 2a-c was performed in order to attempt a
rationalization of the inhibitory activity of the two series of compounds on
geometrical grounds. As the substituted ureido group was invariant in all the cases,
this group was omitted in the theoretical calculations and the simplified structures
8a-c and 9a-c were modeled. The energy profiles for rotation around the C3-X
(X=S, SO2) bond were initially determined on models unsubstituted at the 5 and 6
positions of the heterocyclic ring. Then, after addition of the 5- and/or the 6-phenyl
groups to the minima located in the profiles, the structures were optimized allowing

Ureidopyridazine Derivatives as Acyl-CoA: cholesterol acyltransferase Inhibitors
89
to determine the minimum energy conformations reported in Table 2. The data
show that the presence of the phenyl groups at C5 and C6 does not influence the
behavior of the substituent at C3 (compare, for example, the W 1 and W 2 values of
8aA with those of 8bA and 8cA); the only geometrical effect of having one phenyl
group instead of two is a smaller deviation from planarity of the phenyl with respect
to the pyridazine ring. The phenyl groups can assume two orientations
characterized by opposite values of W 5 and W 6 yielding, however, almost
isoenergetic conformations (compare, for example, 8aA with 8aB or 8aC with 8aD).
Two possible orientations of the C3 substituent were found in the case of 8 as well
as of 9. For the sulfides 8 the differences in energy between the two orientations
(see, for example, 8aA vs. 8aC) is large enough (about 3.8 kcal/mol) to ensure that
only one orientation gives conformers significantly populated, those characterized
by W 1 | 3°; in the case of the sulfones 9, instead, the second orientation (see, for
example, 9aC), characterized by W 1 | -50° gives a not negligible contribution to the
overall population being only about 1.2 kcal/mol less stable than the preferred one
characterized by W 1 | 45° (see, for example, 9aA).
Tab. 2. Relative energy and selected geometrical data of the preferred
conformations of compounds 8a-c and 9a-c.
R2
R1
N
N
X
H3C
8a-c , 9a-c
Conformation Erel
(kcal/mol)
R1 R2
Ph Ph
X
S
W 1a (°) W 2b (°) W 5c (°) W 6d (°)
8aA
8aB
8aC
0.00
0.06
3.76
3
-158
-158
-167
-50
50
-41
42
4
-169
-50
-41

90
Arianna Gelain et al.:
8aD
8bA
8bB
8bC
8bD
8cA
8cB
8cC
8cD
9aA
9aB
9aC
9aD
9bA
9bB
9bC
9bD
9cA
9cB
9cC
9cD
3.90
0.00
0.01
3.90
3.99
0.00
0.01
3.80
3.86
0.00
0.01
1.15
1.19
0.00
0.08
1.22
1.24
0.00
0.04
1.15
1.19
-168
-165
-158
-157
-164
-166
-157
-158
-167
-166
-168
-167
-156
-154
-168
-168
-155
-154
-168
-167
-155
-155
50
-36
37
-37
37
-
42
-
Ph
H
H
S
S
5
3
-
-172
-168
1
-
-
Ph
-22
20
-20
20
-42
42
42
-41
-
3
-
-167
-168
-
-
Ph Ph SO2 44
-48
49
49
-48
-34
33
34
-34
-
46
-47
-53
Ph
H
H
SO2 44
43
-
-51
-
-48
-
Ph SO2 46
21
-21
-20
21
44
-
-52
-50
-
-
a) Torsional angle defined by N2-C3-X-CH. b) Torsional angle defined by C3-X-CH-
CH2. c) Torsional angle defined by C4-C5-C1’-C2’. d) Torsional angle defined by
C5-C6-C1’’-C2’’.
In the hypothesis that the ureido function of all the compounds interacts in the same
way at the binding site inducing a similar orientation of the alkyl chain, we
performed a comparison of the geometry of the conformation 8aA of 8a with the
two conformations 9aA and 9aC of 9a by superimposing the alkyl chain and

Ureidopyridazine Derivatives as Acyl-CoA: cholesterol acyltransferase Inhibitors
91
evaluating the differences in the orientation of the diphenylheterocyclic moiety
(Figure 1). The distances between the centroids of the phenyl groups of the
molecules in comparison were measured and are reported in Figure 1. The
comparison of 8aA with 9aA (Figure 1A) as well as with 9aC (Figure 1B) shows a
correspondence of the 6-phenyl group of the two molecules. On the contrary, the 5-
phenyl group is oriented in different ways.
Fig. 1. Superimposition of conformation 8aA with conformations 9aA and 9aC (the
numbers near the phenyl groups represent the distances in Å between their
centroids).
A
B
2.99
3.55
0.54
0.62
8aA vs. 9aA
8aA vs. 9aC
In conclusion, the presence and the orientation of the 5-phenyl group emerge as
the main factors which modulate activity. Additional influence on the activity might
derive from the different tendency of the phenyl groups to deviate from planarity
with respect to the pyridazine ring.
Experimental
1H-NMR spectra were recorded on a Bruker AC200 spectrometer; chemical
shifts are reported as G (ppm), using the solvent as internal standard. Merck F-254
commercial plates were used for analytical TLC to follow the course of reaction and
check product purity. Silica gel 60 (Merck, 230-400 mesh) was used for flash

92
Arianna Gelain et al.:
chromatography. Elemental analyses of all new compounds were within ± 0.4 of the
theoretical values. The structures of all compounds were consistent with their
analytical and spectroscopic data.
General procedure for the synthesis of the thioderivatives 1a-c and 2a-c.
A solution of J-valerolactone (4.8 mL, 50 mmol) and n-heptylamine (9 mL, 60
mmol) in toluene (10 mL) was refluxed for 18 h in a nitrogen atmosphere. After
cooling, ethyl acetate (60 mL) was added to the mixture, which was washed in
sequence with 1 N HCl (3 u 10 mL) and brine (3 u 10 mL). After drying over sodium
sulfate and evaporation of the solvent, N-heptyl-4-hydroxypentanamide (3) was
1
obtained (8.9 g, 82%). H-NMR (CDCl3) G : 0.85 (t, 3H); 1.20 (d, 3H); 1.25-1.35 (m,
9H); 1.40-1.55 (m, 2H); 1.60-1.85 (m, 2H); 2.35 (t, 2H); 3.20 (q, 2H); 3.78-3.85 (m,
1H); 6.06 (m, 1H).
To a mixture of LiAlH4 (0.26 g, 6.9 mmol) in anhydrous THF (12 mL) under nitrogen
a solution of 3 (0.75 g, 3.5 mmol) in anhydrous THF (4 mL) was added dropwise.
The mixture was then refluxed for 18 h. After cooling to 0 °C, a 10% aqueous
solution of Na2SO4 (3 mL) was added, the solid filtered off and the mixture
extracted with ethyl acetate (3 u 10 mL). The organic layer was washed with
aqueous NaCl (3 u 5 mL), dried over sodium sulfate and evaporated under vacuum
1
to give N-heptyl-4-hydroxypentanamine (4) (0.56 g, 80%). H-NMR (CDCl3) G : 0.85
(t, 3H); 1.18 (d, 3H); 1.20-1.35 (m, 8H); 1.40-1.55 (m, 4H); 1.70-1.80 (m, 2H); 2.48-
2.65 (m, 3H); 2.75-2.85 (m, 1H); 3.68-3.78 (m, 1H).
To a solution of 4 (0.35 g, 1.74 mmol) in CH2Cl2 (2.25 mL) cooled to 0 °C, 2,4-
difluorophenyl isocyanate (0.21 mL, 1.74 mmol) was slowly added under nitrogen.
The mixture was stirred for 1 h and then poured into 1 N HCl (5.5 mL) and
extracted with ethyl acetate (3 u 5 mL). The organic layer was washed in sequence
with water and brine (3 u 5 mL). After drying over sodium sulfate and evaporation of

Ureidopyridazine Derivatives as Acyl-CoA: cholesterol acyltransferase Inhibitors
93
the solvent, the oily yellow residue was purified by flash chromatography (eluent
CH2Cl2/CH3OH
98/2)
to
give
N-(2,4-difluorophenyl)-N’-heptyl-N’-(4-
1
hydroxypentyl)urea (5) (0.34 g, 55%). H-NMR (CDCl3) G : 0.85 (t, 3H); 1.23 (d, 3H);
1.25-1.85 (m, 15H); 3.25-3.45 (m, 4H); 3.82-3.95 (m, 1H); 6.65-6.70 (br s, 1H);
6.80-6.87 (m, 2H); 7.98-8.08 (m, 1H).
To a solution of 5 (0.310 g, 0.87 mmol) and CBr4 (0.348 g, 1.05 mmol) in CH2Cl2
(7.2 mL) under nitrogen, a solution of PPh3 (0.275 g, 1.05 mmol) in CH2Cl2 (2.0 mL)
was added slowly and the mixture stirred for 3 h at room temperature. The so
obtained oily mixture was purified by flash chromatography (eluent petroleum
ether/EtOAc 9/1) to give N-(2,4-difluorophenyl)-N’-heptyl-N’-(4-bromopentyl)urea
1
(6) (0.170 g, 47%). H-NMR (CDCl3) G : 0.85 (t, 3H); 1.20-1.90 (m, 17H); 3.25-3.40
(m, 4H); 4.10-4.25 (m, 1H); 6.40.6.45 (br s, 1H); 6.80-6.85 (m, 2H); 8.00-8.08 (m,
1H).
A mixture of the appropriate pyridazinethiol [11] (7a-c, 0.12 mmol), in turn obtained
from the corresponding pyridazinones [8, 13, 14], anhydrous K2CO3 (0.065 mg,
0.47 mmol), and 6 (0.10 g, 0.24 mmol) in anhydrous DMF (0.5 mL) was stirred at
80 °C for 6 h. To the cooled solution, water was added (2 mL) and the mixture was
extracted with CH2Cl2 (3 u 10 mL). After drying, the solvent was evaporated under
vacuum to give the final compounds (1a-c), which were purified by flash
chromatography (eluent cyclohexane/EtOAc 75/25).
N-(2,4-Difluorophenyl)-N’-heptyl-N’-^ 4-[(5,6-diphenylpyridazin-3-yl)thio]pentyl` urea
1
(1a), H-NMR (CDCl3) G : 0.85 (t, 3H); 1.20-1.40 (m, 9H); 1.50-1.75 (m, 6H); 1.85-
1.95 (m, 2H); 3.25-3.45 (m, 4H); 4.35-4.45 (m, 1H); 6.40-6.45 (br s, 1H); 6.75-6.85
(m, 2H); 7.15-7.20 (m, 2H); 7.25-7.40 (m, 9H); 7.98-8.08 (m, 1H).

94
Arianna Gelain et al.:
N-(2,4-Difluorophenyl)-N’-heptyl-N’-^ 4-[(5-phenylpyridazin-3-yl)thio]pentyl` urea
1
(1b), H-NMR (CDCl3) G : 0.85 (t, 3H); 1.20-1.90 (m, 17H); 3.25-3.40 (m, 4H); 4.35-
4.40 (m, 1H); 6.40-6.45 (br s, 1H); 6.75-6.85 (m, 2H); 7.40-7.65 (m, 6H); 7.98-
8.8.08 (m, 1H); 9.12 (s, 1H).
N-(2,4-Difluorophenyl)-N’-heptyl-N’-^ 4-[(6-phenylpyridazin-3-yl)thio]pentyl` urea
1
(1c), H-NMR (CDCl3) G : 0.85 (t, 3H); 1.20-1.90 (m, 17H); 3.25-3.40 (m, 4H); 4.35-
4.40 (m, 1H); 6.40-6.45 (br s, 1H); 6.75-6.85 (m, 2H); 7.35 (d, 1H); 7.45-7.55 (m,
3H); 7.62 (d, 1H); 7.95-8.05 (m, 3H).
To a solution of the appropriate 1a-c (0.083 mmol) in methanol (2.5 mL) oxone
(0.102 g, 0.17 mmol) was added portionwise and the mixture stirred for 4 h. The
residue was treated with methanol (10 mL) and the insoluble filtered off. After
evaporation of the solvent, 2 was purified by flash chromatography (eluent
cyclohexane/EtOAc 60/40) (see Table 1).
N-(2,4-Difluorophenyl)-N’-heptyl-N’-^ 4-[(5,6-diphenylpyridazin-3-
1
yl)sulfonyl]pentyl` urea (2a), H-NMR (CDCl3) G : 0.85 (t, 3H); 1.20-2.20 (m, 17H);
3.20-3.40 (m, 4H); 4.00-4.05 (m, 1H); 6.40-6.45 (br s, 1H); 6.75-6.85 (m, 2H); 7.10-
7.50 (m, 10H); 7.95-8.05 (m, 1H); 8.18 (s, 1H).
N-(2,4-Difluorophenyl)-N’-heptyl-N’-^ 4-[(5-phenylpyridazin-3-yl)sulfonyl]pentyl` urea
1
(2b), H-NMR (CDCl3) G : 0.85 (t, 3H); 1.20-2.10 (m, 17H); 3.20-3.40 (m, 4H); 3.95-
4.05 (m, 1H); 6.40-6.45 (m, 1H); 6.75-6.85 (m, 2H); 7.55-7.60 (m, 3H); 7.65-7.70
(m, 2H), 7.95-8.05 (m, 1H); 8.35 (s, 1H); 9.60 (s, 1H).
N-(2,4-Difluorophenyl)-N’-heptyl-N’-^ 4-[(6-phenylpyridazin-3-yl)sulfonyl]pentyl` urea
1
(2c), H-NMR (CDCl3) G : 0.85 (t, 3H); 1.20-2.10 (m, 17H); 3.20-3.40 (m, 4H); 3.90-

Ureidopyridazine Derivatives as Acyl-CoA: cholesterol acyltransferase Inhibitors
95
4.00 (m, 1H); 6.40 (br s, 1H); 6.75-6.85 (m, 2H); 7.55-7.60 (m, 3H); 7.90-8.02 (m,
1H), 8.05-8.25 (m, 4H).
Enzyme assays
In vitro assay against rat ACAT. Microsomes prepared from rat liver were used
as a source of the enzyme. The activity of the ACAT inhibitors against rat ACAT
was measured according to a previously described method [15]. GERI-BP001M
was used as reference compound.
Computational methods
All calculations were carried out using the Gaussian 03 [16] program package.
The conformational space of compounds 8a-c, 9a-c was explored through
optimizations at the B3LYP level with the 6-31G* basis set. The energy profiles for
rotation around the C3-X bond were initially determined on simplified molecules
unsubstituted at the 5 and 6 positions of the heterocyclic ring. Then, after addition
of the 5- and/or 6-phenyl groups to the minima located in the profiles, the structures
were fully optimized allowing to determine the minimum energy conformations of
compounds 8-9.
Acknowledgements
This work was partially supported by Italy-Korea Joint Research Program and
KRIBB Initiative Research Program. The Authors also aknowledge the financial
support from the University of Milan (FIRST 2006) and Pavia (FAR 2006).
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Received August 29th, 2006
Accepted September 6th, 2006