Inhibitors of acyl-CoA:Cholesterol O-acyl transferase (ACAT) as hypocholesterolemic agents. CI-1011: An acyl sulfamate with unique cholesterol-lowering activity in animals fed noncholesterol-supplemented diets

Full text of DOI:10.1021/jm960674d

J . Med. Chem. 1996, 39, 5031-5034
5031
methylethyl)phenyl ester (7, CI-1011). This compound
is highly stable in acidic or basic solution and displays
excellent in vivo efficacy in standard cholesterol-fed rat
models. Of particular note, however, was the finding
that 7 potently reduced plasma cholesterol in chow-fed
rats and in rabbits fed a cholesterol-free, casein-contain-
ing diet characterized by both hepatic overproduction
of apo B-containing lipoproteins and delayed lipoprotein
clearance.
In h ibitor s of Acyl-CoA:Ch olester ol O-Acyl
Tr a n sfer a se (ACAT) a s
Hyp och olester olem ic Agen ts. CI-1011:
An Acyl Su lfa m a te w ith Un iqu e
Ch olester ol-Low er in g Activity in An im a ls
F ed Non ch olester ol-Su p p lem en ted Diets
Helen T. Lee,† Drago R. Sliskovic,*,†
J oseph A. Picard,† Bruce D. Roth,†
A consideration of degradation products 3 and 4
indicated that hydrolysis of the carbamate group in 1
was the most likely explanation for the acid-catalyzed
degradation. A two-pronged strategy was initiated to
stabilize the C(O)-O bond of the carbamate. The first
strategy employed was the steric protection of the
C(O)-O bond by bulky flanking groups on the aryl ring
of the carbamate phenol. As can be seen from Table 1,
compounds 2 (isopropyl flanking groups) and 54 (methyl
flanking groups) degraded rapidly in neutral solution
with only 37% and 20% of 2 and 5, respectively,
remaining after 24 h. The 2,6-di-tert-butyl compound
(6)4 and sodium salt (1) were perfectly stable under
these conditions over 24 h. However, in acidic solution
(Table 1), 1 degraded at the same rate as the free acid
(2) while 6 showed only minimal degradation (<4%)
under these conditions. Thus, we were able to stabilize
the aryl carbamate in 1 by the incorporation of bulky
2,6-di-tert-butyl flanking groups.
Wendell Wierenga, J ames L. Hicks,‡
Richard F. Bousley,§ Katherine L. Hamelehle,§
Reynold Homan,§ Cecilia Speyer,§
Richard L. Stanfield,§ and Brian R. Krause§
Departments of Medicinal Chemistry,
Radiochemistry, and Vascular and Cardiac Diseases,
Parke-Davis Pharmaceutical Research,
Division of Warner-Lambert Company,
2800 Plymouth Road, Ann Arbor, Michigan 48105
Received September 26, 1996
We have previously described the design and synthe-
sis of a new class of ACAT inhibitors which possess very
different physicochemical properties when compared to
the more “typical” inhibitors, which have been uniformly
lipophilic and possess little, if any, aqueous solubility.1
From this new series, compound 1 was shown to have
a log P of 2.98 and an aqueous solubility of 21 mg/mL
over a pH range of 6.87-9.85. In addition to these novel
physicochemical properties and despite weak ACAT
inhibition in vitro, compound 1 was one of the most
effective lipid-regulating agents thus far discovered.
However, despite this impressive efficacy, continued
pharmacological evaluation was complicated by pH
dependent stability of 1. The corresponding free acid
An alternative strategy was to replace the phenolic
oxygen of the carbamate by a methylene group.
A
retrosynthetic analysis of a prototype compound 7
indicated that bond disconnection of the amide yielded
two synthons readily synthesized from commercially
available starting materials. The synthetic route to 7
is shown in Scheme 1. The requisite acid chloride 8 was
prepared in five steps from commercially available 2,4,6-
triisopropylbenzoyl chloride (9). Hydride reduction of
9 gave the alcohol in 98% yield, which was then treated
with PBr3 in ether to give the corresponding bromide
in 97% yield. Nucleophilic displacement of the bromide
by cyanide (KCN/DMSO), acidic hydrolysis, and subse-
quent acid chloride formation gave the required acid
chloride 8 in 50% overall yield. The known sulfamate
4 was prepared according to the method of Hedayatul-
lah.5 Compounds 4 and 8 were then coupled under basic
conditions to give 7 in 80% yield.
(2) of 1 degraded rapidly in neutral aqueous solution.
Conversion to the sodium salt (1) prevented this deg-
radation. Solution stability studies in acidic aqueous
media have shown that 1 degrades into two products
identified as 2,6-diisopropylphenol 3 and sulfamate 4.2
The problems associated with this acidic degradation
are compounded by the fact that compounds 1, 3,
and 4 induced various hepatic cytochrome P450
isozymes.3
In an effort to overcome the inherent chemical insta-
bility of 1, a study was initiated to identify compounds
with equivalent (or better) in vitro and in vivo activities
but greater solution stability, especially at pH <7. This
paper describes the resulting discovery of [[2,4,6-tris-
(1-methylethyl)phenyl]acetyl]sulfamic acid, 2,6-bis(1-
This compound was completely stable in solution over
a broad range of pH values (4.2-12) and temperatures
(25-60 °C) over extended periods of time (up to 72 h).
ACAT inhibition, by 7, was demonstrated using both
microsomal and cellular assays. In the microsomal
assay, using livers from cholesterol-fed rats, 7, like
compound 1, was found to be a weak ACAT inhibitor
with an IC50 value of 12.0 µM. However, it was
subsequently found that the IC50 values obtained for
this compound are highly dependent on the concentra-
tion of microsomes used in the assay. Thus, the IC50 of
this compound is 0.7 µM when 0.2 mg/mL of microsomes
are used instead of the standard 1 mg/mL. Restoring
the membrane concentration by adding reconstituted
lipids back to the media gave an IC50 value close to 12.0
µM. In retrospect, this finding is not surprising since
other authors have speculated that inhibitors of mem-
brane-bound enzymes (such as ACAT) reach the enzyme
† Department of Medicinal Chemistry.
‡ Department of Radiochemistry.
§ Department of Vascular and Cardiac Diseases.
S0022-2623(96)00674-7 CCC: $12.00 © 1996 American Chemical Society

5032 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26
Ta ble 1. Solution Degradation Studies
Communications to the Editor
Ta ble 2. Dose-Response for 7 in Cholesterol-Fed Rats: Acute
Screena
% unchanged at pH 0.4a
% unchanged at pH 6.4b
compd
no.
treatment
group
dose
(mg/kg)
plasma cholesterol
(mg/dL)
0 h 2 h 4 h 8 h 24 h 0 h 2 h 4 h 8 h 24 h
% change
1
2
5
6
100
95
93
92 83 68
88 80 66
71 57 37
25 100 100 100 100 100
PCC controls
chow controls
183 ( 14
76 ( 5
23
5
95
94
87
79
85
65
99
74
48
99
37
20
98
-58
-32
-56
-60
-64
-72
7
7
7
7
7
0.1
0.3
1
3
10
124 ( 15b
81 ( 2c
72 ( 5c
66 ( 5c
51 ( 3c,d
100 100 99 98
97 100 100
a
pH 0.4 ) 50% 1 M HCl/50% acetonitrile. b pH 6.4 ) 50% water/
50% acetonitrile.
through the membrane and not the aqueous volume
surrounding the membrane.6 Thus, activity of a mem-
brane-bound inhibitor should depend on both the total
inhibitor concentration and the amount of membrane
available for inhibitor adsorption. The amount of
inhibitor bound to the membrane can be determined at
various membrane concentrations from a single dose-
response curve if the inhibitor concentration is ex-
pressed in terms of moles of inhibitor per mole of
membrane (mol %).7
Such an analysis showed that ACAT was inhibited
50% when the microsomal membrane contained 3.9 mol
% 7. In addition to this observation, it has been shown
that this compound also binds avidly to bovine serum
albumin (BSA) which is present in the assay at a
concentration of 50 µM. Thus, as with the membrane
binding, the IC50 values are overestimated because of
the BSA binding. At 20 µM BSA, the IC50 in IC-21
macrophages was 0.76 µM; this value decreased to 60
nM when no BSA was in the assay. In order to
determine this directly, the efflux of [3H]-7 from IC-21
cells was determined in the presence and absence of
BSA (20 µM). It was determined that 90% of [3H]-7
remained associated with the cells in the absence of
BSA, while in the presence of BSA, only 3% of [3H]-7
remained cell-associated. In addition, in IC-21 mac-
rophages, if the total inhibitor concentration in the
a
b
Data are mean ( SEM, n ) 5/group. p < 0.05. c p < 0.01 vs
d
controls (t-test). Significantly lower than chow controls, p )
0.0024 (t-test).
assay sample is considered, the IC50 values for 7 and
CI-976, a reference ACAT inhibitor,8 were 3.3 vs 0.3 µM,
respectively. However, when [3H]-7 and [14C]CI-976
were used to determine ACAT inhibition on the basis
of cell-associated ACAT inhibitor, it was shown that
cellular ACAT was inhibited 50% when cells contained
54 pmol of CI-976/mg of cell protein or 14 pmol of 7/mg
of cell protein. Thus, on the basis of cell-associated
ACAT inhibition, 7 is 3.5-fold more potent than CI-976.
These latter results may be a more realistic measure of
relative inhibitory strength than determinations based
on the total inhibitor concentration in the sample since
ACAT can only be inhibited by the presence of inhibitor
within the cell. Collectively, these data indicate that 7
is indeed a potent ACAT inhibitor and that the previous
microsomal data is more a measure of the affinity of 7
for BSA than of ACAT inhibition.7
As has been done with most ACAT inhibitors, efficacy
for 7 was demonstrated in several, now standard,
cholesterol-fed rat models. Acute efficacy measured the
ability of a single dose of 7 to prevent the overnight rise
in dietary cholesterol induced by a single high fat, high
cholesterol meal. As shown in Table 2, 7 is remarkably
Sch em e 1

Communications to the Editor
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26 5033
Ta ble 3. Dose-Response for 7 in Cholesterol-Fed Rats: Chronic Screena
exp no.
1
treatment group
dose (mg/kg)
TC
%∆
HDL-C
%∆
non-HDL-C
%∆
PCC controls
chow controls
7
7
7
7
7
PCC controls
chow controls
7
7
7
7
222 ( 37
62 ( 2b
14 ( 1
29 ( 1b
16 ( 1
20 ( 1b
25 ( 2b
33 ( 2b
36 ( 4b
17 ( 1
46 ( 3b
16 ( 1
15 ( 2
15 ( 1
18 ( 1
208 ( 38
33 ( 2b
-72
-41
-60
-61
-59
-69
+108
+17
-84
-45
-66
-70
-72
-84
0.1
0.3
1
3
10
131 ( 10c
90 ( 6b
114 ( 9c
70 ( 7b
+42
+76
86 ( 8b
61 ( 9b
92 ( 8b
+140
+155
59 ( 8b
69 ( 6b
33 ( 5b
2
535 ( 59
518 ( 59
84 ( 3b
-84
+3
+16
-38
-40
+178
-3
-12
-12
+7
39 ( 1b
-93
+3
+17
-38
-41
0.001
0.01
0.03
0.1
551 ( 69
619 ( 60
334 ( 25c
323 ( 38
535 ( 68
604 ( 60
320 ( 25
306 ( 39c
a
b
Values are the mean ( SEM, n ) 6/group. p < 0.01 vs PCC controls (t-test). c p < 0.05.
Ta ble 4. Effect of 7 in Normal, Chow-Fed Ratsa
potent in this model with efficacy observed at the lowest
dose tested (0.1 mg/kg) and improving with increasing
dose. The calculated ED50 in this screen was 0.4 mg/
kg. For comparison, it can be noted that the ED50
values for the ACAT inhibitors CI-976, CL 277082,9
DuP-128, and 11 are 77, 16, 15, and 2 mg/kg, respec-
tively. At the highest dose tested (10 mg/kg), the
resultant plasma cholesterol level was significantly
lower than the chow control group. Compound 7 was
also capable of reducing total and non-HDL-C and
elevating HDL-C after multiple oral doses in rats with
preestablished dyslipidemia (Table 3). The ED50 value
for non-HDL-C reduction was 0.09 mg/kg. The ED50
values for the ACAT inhibitors, CL 277082,8 DuP-128,1
and 1,1 are 17, 17, and 1.1 mg/kg, respectively. The
lowest effective dose for HDL-C elevation was 0.3 mg/
kg. For comparison, the lowest effective dose for gem-
fibrozil for elevating HDL-C was 30 mg/kg.10
The relevancy of the cholesterol-fed rat in predicting
the human response to ACAT inhibitors has been called
into question by the finding that CL 27708211 and DuP-
12812 had little or no effect on cholesterol absorption or
plasma cholesterol in normolipidemic volunteers. The
same question may pertain to other cholesterol-fed
animal models; e.g., these compounds, as well as 7,13
also lower plasma cholesterol effectively in cholesterol-
fed hamsters14,15 and rabbits.16 Therefore, in order to
provide some degree of assurance that 7 is preclinically
unique and of potential clinical utility, we now report
efficacy for 7 in two alternative, non-cholesterol-fed
animal models in which drugs (HMG-CoA reductase
inhibitors and fibrates) known to reduce LDL cholesterol
in humans are active, namely, normal, chow-fed rats
and casein-fed rabbits. We believe that efficacy in both
models provides suggestive evidence for the extent of
liver drug exposure and consequent inhibition of hepatic
ACAT, VLDL secretion, and/or “direct” LDL production.
treatment
group
dose
(mg/kg)
plasma TC
(mg/dL)
plasma TG
(mg/dL)
%∆
%∆
controls
7
7
59 ( 4
49 ( 3
44 ( 3b
41 ( 4b
53 ( 2
57 ( 3
50 ( 2
67 ( 10
58 ( 2
55 ( 3
169 ( 10
95 ( 8b
3
10
30
3
10
30
3
-16
-25
-30
-9
-44
-55
-66
-25
-26
-54
-31
-22
-37
75 ( 13b
58 ( 10b
127 ( 8b
125 ( 6b
78 ( 10b
116 ( 16b
131 ( 6b
107 ( 13b
7
CL 277082
CL 277082
CL 277082
DuP-128
DuP-128
DuP-128
-3
-15
+15
-2
10
30
-7
a
Values are the mean ( SEM, n ) 6/group TC ) total
b
cholesterol; TG ) triglycerides. Significantly different from
controls, p < 0.05 (ANOVA).
Ta ble 5. Comparison of ACAT Inhibitors in Rabbits Fed a
Cholesterol-Free Casein Dieta
pretreatment posttreatment
plasma
cholesterol
(mg/dL)
plasma
cholesterol mean percent
(mg/dL)
treatment
group
dose
(mg/kg)
change (%)
controls
7
7
242 ( 25
215 ( 25
250 ( 40
209 ( 28
227 ( 21
231 ( 32
251 ( 38
223 ( 21
254 ( 36
252 ( 372
396 ( 44
184 ( 35
171 ( 35
118 ( 20
284 ( 36
342 ( 53
320 ( 72
304 ( 36
237 ( 58
210 ( 40
+64 ( 6
1
3
10
1
3
10
1
-15 ( 14b
-33 ( 6c
-37 ( 14c
+52 ( 9
7
CL 277082
CL 277082
CL 277082
DuP-128
DuP-128
DuP-128
+31 ( 18
+33 ( 33
+43 ( 18
+4 ( 27
3
10
-12 ( 20
a
b
See ref 17 for composition of diet. p < 0.10. c p<0.05.
is of purely endogenous origin.17 The LDL cholesterol
increases severalfold (>85% of total cholesterol), due in
large part to the hypersecretion of apoB-containing
lipoproteins which are enriched in ACAT-derived cho-
lesteryl esters.17,18
The clearance of LDL is also delayed
in this model.18 The role of ACAT in the etiology of the
endogenous hypercholesterolemic condition was con-
firmed by administering CI-976, a potent ACAT inhibi-
tor, which decreased LDL cholesterol by 43% at 50 mg/
kg without affecting biliary cholesterol absorption.17
When 7 was compared to CL 277082 and DuP-128 in
this model, only 7 lowered plasma cholesterol concen-
trations (Table 5). Plasma triglycerides are typically
low in this animal model and unaffected by ACAT
inhibitors. Preliminary evidence suggests that 7 de-
creases the direct secretion of LDL by the liver and also
enhances LDL clearance in this animal model.19 This
latter finding is unexpected for an ACAT inhibitor but
supports the view that the hepatic concentration of
With respect to ACAT inhibitors, we previously
reported that CL 277082 failed to lower plasma choles-
terol in normal chow-fed rats but that it did reduce
plasma triglycerides.9 When compared to CL 277082
and DuP-128 in this model, 7 was the only compound
that lowered plasma cholesterol (Table 4). However, all
compounds reduced plasma triglycerides, with 7 being
the most potent. We are unaware of any previous
reports of ACAT inhibitors lowering plasma cholesterol
in chow-fed rats at these doses.
In the second model, rabbits were fed a cholesterol-
free, purified diet which contains casein as the sole
protein source. The resulting hyperlipidemia observed

5034 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26
Communications to the Editor
(6) Mason, P. R.; Rhodes, D. G.; Herbette, L. G. Reevaluating
Equilibrium and Kinetic Binding Parameters for Lipophilic
Drugs Based on a Structural Model for Drug Interaction with
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(7) Homan, R.; Hamelehle, K. L. Effect of Membrane Binding on
Acyl CoA:Cholesterol Acyl-Transferase Inhibitor Activity. Ab-
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Lipid Metabolism, Houston, TX, November 7-10, 1995, p. 61.
(8) Krause, B. R.; Anderson, M.; Bisgaier, C. L.; Bocan T.; Bousley,
R.; DeHart, P.; Essenburg, A.; Hamelehle, K. L.; Homan, R.;
Kieft, K.; McNally, W.; Stanfield, R. L.; Newton, R. S. In vivo
evidence that the lipid-regulating activity of the ACAT inhibitor
CI-976 in rats is due to inhibition of both intestinal and liver
ACAT. J . Lipid Res. 1993, 34, 279-294.
(9) Krause, B. R.; Black, A.; Bousley, R.; Essenburg, A. D.; Cornicelli,
J . A.; Holmes, A.; Homan, R.; Kieft, K. A.; Sekerke, C.; Shaw-
Hes, M. K.; Stanfield, R. L.; Trivedi, B. K.; Woolf, T. Divergent
Pharmacological Activities of PD 132301-2 and CL 277,082,
Urea Inhibitors of Acyl CoA:Cholesterol Acyl-Transferase. J .
Pharmacol. Exp. Ther. 1993, 267, 734-743.
(10) Krause, B. R.; Bousley, R.; Kieft, K.; Robertson, D. G.; Stanfield,
R. L.; Urda, E.; Newton, R. S. Comparison of Lifibrol to Other
Lipid-Regulating Agents in Experimental Animals. Pharmacol.
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(11) Harris, W. L.; Dujovne, C. A.; von Bergmann, K.; Neal, J .;
Akester, J .; Windsor, S. L.; Greene, D.; Look, Z. Effects of the
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mans. Clin. Pharmacol. Ther. 1990, 48, 189-194.
(12) Hainer, J . W.; Terry, J . G.; Connell, J . M.; Zyruk, H.; J enkins,
R. M.; Shand, D. L.; Gillies, P. J .; Livak, K. J .; Hunt, T. L.;
Crouse, J . R., III Effect of the acyl CoA:cholesterol acyl-
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Kieft, K.; Anderson, M. K.; Lee, H; Homan, R. CI-1011: A Novel
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ACAT-derived cholesteryl esters in the liver may de-
termine LDL receptor number.20
In conclusion, we have identified a compound 7, which
displays potent ACAT inhibition in cellular assays
where the activity is determined on the basis of cell-
associated ACAT inhibitor. In the typical microsomal
assay, the potency of 7 is highly dependent on the
amount of microsomal membrane and albumin present
in the assay. When the concentrations of both of these
assay components are decreased, the IC50 also de-
creases. A similar finding has recently been reported
that also shows the dependence of the IC50 on the lipid
composition of the assay system.21
The compound is very efficacious in a variety of
cholesterol-fed animal models; however, efficacy in these
models has not yet been translated into efficacy in hu-
man trials. HMG-CoA reductase inhibitors and fibrates
are two classes of hypolipidemics that are efficacious
in noncholesterol-fed animal models and are known to
reduce LDL cholesterol in man. Thus, in order to pro-
vide some level of confidence in the clinical utility of
this compound, it was evaluated in two noncholesterol-
fed animal models, namely, normal, chow-fed rats and
casein-fed rabbits. Compound 7 was highly efficacious
when evaluated in these models, whereas two previous
drug candidates, CL 277082 and DuP-128, which failed
in the clinic, did not show any LDL lowering. The
relationship between efficacy, for 7, in noncholesterol-
fed animal models and plasma cholesterol lowering in
humans is currently under investigation in clinical
trials.
Su p p or tin g In for m a tion Ava ila ble: Full experimental
details (3 pages). Ordering information is given on any current
masthead page.
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J M960674D