Oxidosqualene cyclase (OSC) inhibitors for the treatment of dyslipidemia

Article abstract of DOI:10.2533/000942905777676858

Novel inhibitors of oxidosqualene cyclase (OSC) for the treatment of dyslipidemia are reported. Starting point for the chemistry program was a set of compounds derived from a fungicide project which, in addition to high affinity for OSC from Candida albicans, also showed high affinity for the human enzyme (hOSC). Here the evaluation process of different scaffolds is outlined for two representative series, the phenyl substituted benzo[d]isothiazoles and the aminocyclohexanes. The most promising compounds derived from the latter series were further profiled in vivo and showed promising properties with respect to modulation of lipid parameters. Schweizerische Chemische Gesellschaft.

Full text of DOI:10.2533/000942905777676858

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CHIMIA 2005, 59, No. 3
Chimia 59 (2005) 72–76
© Schweizerische Chemische Gesellschaft
ISSN 0009–4293
Oxidosqualene Cyclase (OSC) Inhibitors
for the Treatment of Dyslipidemia
Henrietta Dehmlowa§*, Jean Ackermanna, Johannes Aebia, Denise Blum-Kaelina,
Alexander Chucholowskib, Philippe Coassoloa, Peter Hartmana, Manfred Kansya,
Hans Peter Märkia, Olivier Morandc, Elisabeth Von der Marka, Narendra Pandaya, Armin Rufa,
Ralf Thomaa, and Tanja Schulz-Gascha
§Mettler Toledo Award Winner (Oral Presentation)
Abstract: Novel inhibitors of oxidosqualene cyclase (OSC) for the treatment of dyslipidemia are reported. Starting
point for the chemistry program was a set of compounds derived from a fungicide project which, in addition to high
affinity for OSC from Candida albicans, also showed high affinity for the human enzyme (hOSC). Here the evaluation
process of different scaffolds is outlined for two representative series, the phenyl substituted benzo[d]isothiazoles
and the aminocyclohexanes. The most promising compounds derived from the latter series were further profiled in
vivo and showed promising properties with respect to modulation of lipid parameters.
Keywords: Dyslipidemia · Medicinal chemistry · Oxidosqualene cyclase · Structure-activity relationship
Introduction
observed [2][6], and the clinical benefit as-
sociated with the lowering of LDL-C levels
is now well established for both primary as
well as secondary prevention [2][7][8].
Current standard therapies for the phar-
macologic treatment of lipid abnormalities
effectively modulate only one of the lipid
parameters. So the most widely used lip-
id-modifying drugs, statins (3-hydroxy-3-
methyl gluturyl coenzyme A (HMG-Co-A)
reductase inhibitors) very effectively reduce
plasma LDL-C by 30–45% at standard dose
while affecting the plasma triglyceride level
to a lesser extent. On the other hand, fibrates
(fibrateesterderivatives)reduceplasmalev-
els of triglycerides more effectively, but not
LDL-C levels.Although statins are well tol-
erated at standard doses and adverse events
are rare, side effects reported at high doses
are elevated liver enzyme levels, myopathy
and rhabdomyolisis.
HMG-CoA reductase inhibition, should not
lead to an undesired reduction of isoprenoid
intermediates of cholesterol synthesis and
their metabolites, e.g. coenzyme Q10 [9].
Furthermore, OSC inhibition has an indi-
rect, negative feed-back regulatory mecha-
nism [12] involving 24(S),25-epoxycholes-
terol which potentiates the primary inhibi-
tory effect and reduces the accumulation of
mono-oxidosqualene in the liver. In addi-
tion, potential OSC inhibitors could also
indirectly activate liver X receptor (LXR)
dependent pathways via 24(S),25-epoxy-
cholesterol, a known potent natural agonist
of the nuclear receptor LXR [13][14].
One of the most common cases of death in
the western world is artherosclerotic car-
diovascular disease, accounting for over
30% of deaths [1]. In epidemiological and
prospective studies several risk factors
have been identified which promote the de-
velopment of atherosclerosis [2–5]. These
include, in addition to life habit risk factors
such as obesity, smoking and physical in-
activity, elevated plasma levels of low-den-
sity lipoprotein cholesterol (LDL-C), low
plasma high-density lipoprotein cholesterol
(HDL-C), and elevated concentrations of
plasma triglyceride (TG)-rich lipoproteins.
A strong correlation for the occurrence of
coronary heart disease (CHD) cases with
LDL-C and TG levels in plasma has been
Starting Point and Strategy
A set of compounds derived from a fun-
gicide project [15][16] which in addition to
high affinity for OSC from Candida albi-
cans, also showed high affinity for hOSC
[9][17] served as a starting point for the
chemistryprogram.Commonstructuralfea-
tures of all of these inhibitors are an amine
residue and an electrophilic carbonyl-C-
In this context 2,3-oxidosqualene:lano-
sterol cyclase (OSC; E.C. 5.4.99.7) inhi-
bition, which would allow a concomitant
lowering of both LDL-C and TG levels, was
identified as a potential target to improve
current therapies [9]. OSC, a microsomal
*Correspondence: Dr. H. Dehmlowa
Tel.: + 41 61 688 9040
Fax: + 41 61 688 9748
E-Mail: henrietta.dehmlow@roche.com
membrane-associated enzyme consisting atom embedded in a benzophenone system.
aPharma Division
Preclinical Research
of 732 aa with a size of 83.4 kDa, is loca-
ted down-stream of HMG-CoA reductase
in the biosynthetic pathway of choleste-
rol. It catalyzes the selective cyclization
of the linear substrate 2,3-oxidosqualene
(mono-oxidosqualene, MOS) to lanosterol
[10][11]. Inhibition of OSC, in contrast to
As neither an X-ray structure of hOSC [18]
nor of related enzymes such as the prokary-
otic counterpart of OSC squalene hopene
cyclase (SHC) [19][20] were known at the
start of the project, the optimization process
was guided by a pharmacophore model.
This model was derived by superimposing
F. Hoffmann-La Roche Ltd
CH–4070 Basel
bChemBridge Research Laboratories, LLC (CRL)
16981 Via Tazon
San Diego, CA 92127, USA
cActelion Pharmaceuticals Ltd
Gewerbestrasse 16
CH–4123 Allschwil

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CHIMIA 2005, 59, No. 3
the structure of the folded, high energy con-
former of mono-oxidosqualene (mimicking
an opened protosterol) and 1 (Ro 48-8071)
a
c
d
Amine --- Spacer --- --- Core
as depicted in Fig. 1b. Later analysis of the
F
O
X-ray of 1 in complex with hOSC support-
ed this initial model. The essential interac-
tions of 1 with the protein are depicted in
Fig. 1c and 1d. The hydrogen bond between
the nitrogen of the N,N-methylallylamine
moiety and the carboxylate of the catalytic
acid Asp 455 demonstrates the importance
of the basic amine residue of the inhibi-
tors. The electron-deficient aromatic part
of the benzophenone system is embedded
in a pocket formed by Phe 521 and His
232. Furthermore, the carbonyl moiety of
the benzophenone indirectly interacts with
Ile338 via a water molecule.
N
O
Br
1 (Ro 48-8071)
b
δ+
δ+
δ+
Thegoaloftheoptimizationwastoiden-
tify hOSC inhibitors with increased potency
both in vitro and in vivo, increased metabol-
ic stability and higher drug exposure in the
target organs as compared to 1. As the car-
bonyl moiety of the benzophenone residue
was considered a potential site of metabo-
lism [21] one approach consisted of replac-
ing the benzophenone by other core struc-
tures. Several alternative core structures
including heterocyclic derivatives such as
phenyl substituted benzo[d]isothiazoles,
benzisoxazoles, dioxo-benzo[d]isothiazole,
benzo[b]thiophenes, indazoles, isoxazoles
and indoles as well as substituted indolines,
piperidines, anilines and aminocyclohex-
anes were explored [17][22]. For most core
scaffolds rapid evaluation of different spac-
ers and amine substituents was possible by
parallel synthesis. The process is depicted
for two representative classes, the substi-
tuted benzo[d]isothiazoles and aminocy-
clohexane derivatives.
δ+
δ+
Fig. 1. a) 1 Ro 48-8071; b) Superimposed structures of the folded, high energy conformer of
oxidosqualene (mimicking the opened protosterol) and 1 (Ro 48-8071); c) Binding interactions with
the amine residue; d) Binding interactions with the benzophenone moiety
Chemistry
The synthesis for benzo[d]isothiazoles
is outlined in Scheme 1 [17]. Starting from
3-fluoro-anisole (2), Friedel-Crafts acyla-
tion with 4-bromo benzoyl chloride (3) in
the presence of AlCl3 gave the desired
benzophenone 4. Reaction of 4 with benzyl-
mercaptane in the presence of potassium
t-butylate yielded the thioether derivative
5 which upon treatment with sulfuryl chlo-
ride and ammonia gave benzo[d]isothiazole
(6) [23]. Subsequent cleavage of the meth-
ylether with boron tribromide gave phenol
7, which was subjected to alkylation with
an excess of α,ω-dibromoalkanes to yield
the intermediates 8 that were converted to
the final amines 9 by reaction with different
primary or secondary amines.
Scheme 1. Synthesis of heteroaromatic compounds – benzo[d]isothiazole derivatives. Reagents and
conditions: a) AlCl3, PhNO2, 0 °C to rt, 42%; b) KOt-Bu, BnSH, THF, rt; c) SO2Cl2, CH2Cl2, rt; d) NH3,
EtOH, rt; e) BBr3, CH2Cl2, –78 °C to rt, 73% (from 4); f) α,ω-dibromoalkane, 10% aq. NaOH, N(Bu)4Br,
CH2Cl2, rt, 70%; g) NHR1R2, DMA, rt, 70–88%; (h) KMnO4/SiO2, CH2Cl2, rt, 80%.
Furthermore, intermediates 8 could be
oxidized with KMnO4 to give the bromo-

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CHIMIA 2005, 59, No. 3
alkyloxy dioxo-benzo[d]isothiazoles 10
which were further converted to the final
products 11 by amination. Analogous to
compounds 9, the benzo[d]isothiazoles 13
were derived from benzophenone 12.
For the aminocyclohexane derivatives
with oxygen-linked spacers the synthesis is
depicted in Scheme 2. The synthesis start-
ed from trans-4-aminocyclohexanol (14)
which was converted to the BOC-protected
trans-4-methylaminocyclohexanol (15) by
treatment with ZCl, reduction with LAH
followed by BOC-protection. 15 was alkyl-
ated under phase transfer conditions with
α,ω-dihaloalkanes to yield the bromide 16.
Alternatively, 15 was treated with α,ω-diha-
loalkanes in the presence of NaH in DMF
Scheme 2. Synthesis of aminocyclohexane derivatives with oxygen-linked spacers. Reagents and
conditions: a) ZCl, Na2CO3, THF, H2O, rt, 98%; b) LAH, THF, 0 °C to rt, 80%; c) (BOC)2O, iPrOH,
CH2Cl2, rt, 98%; d) α,ω-dibromoalkane, Bu4NHSO4, NaOH, H2O, rt, 76%; e) NHR1R2, DMA, rt, 92%;
f) TFA, CH2Cl2, rt, 91%; g) R3SO2Cl, iPr2NEt, CH2Cl2, rt, 50–80%; h) R3OCOCl, iPr2NEt, CH2Cl2, rt,
60–75%.
or especially for shorter spacer lengths with
the in situ generated haloalkane-triflates
(from the corresponding haloalkanols with
trifluoromethansulfonic
anhydride/2,6-
di-tert-butylpyridine [24]). The reaction
of bromide 16 with primary or secondary
amines followed by cleavage of the BOC
protecting group gave the intermediate 17 as
TFA salt. 17 was converted to different sul-
fonamides 18 or carbamates 19 by reaction
with sulfonyl chlorides or chloroformates,
respectively. In a similar manner urea, sul-
famide, amide, thiourea or thioamide ana-
logues were prepared (not shown).
Analogous aminocyclohexanes with
carbon-linked spacers were prepared as
depicted in Scheme 3 for compounds with
a pentyl spacer. The synthesis started from
(trans)-4-t-butoxycarbonyl amino-cyclo-
hexane-carboxylic acid (20) which was
converted to its ester prior to N-alkylation
using NaH and methyl iodide. Reduction
of the ester to the aldehyde 21 could be
achieved in a single step with DIBAL-H
or alternatively, via LiBH4 reduction to
the alcohol and re-oxidation using Swern
conditions. Horner-Wadsworth-Emmons
(HWE) reaction of 21 with triethyl phos-
phono acetate yielded the unsaturated ester
22. A second chain elongation of 22 to ester
23 was accomplished analogously. After
hydrogenation of the double bond again a
reduction/oxidation sequence and subse-
quent HWE reaction gave the desired ester
23. Hydrogenation of the double bond and
LAH reduction followed by mesylation of
the alcohol and cleavage of the BOC-pro-
tecting group using standard conditions
yielded the building block 24 as TFA salt.
Different sulfonamides 25 or carbamates 26
were prepared by reaction of 24 with sul-
fonyl chlorides or chloroformates, respec-
tively, followed by treatment with primary
or secondary amines. Again in a similar
manner urea, sulfonamide, amide, thiourea
or thioamide analogues have been prepared
(not shown).
Results and Discussion
The compounds were tested first for the
inhibition of hOSC at a single concentration
(100 nM). The potency of compounds from
Scheme 3. Synthesis of aminocyclohexane derivatives with carbon-linked spacers. Reagents and conditions: a) Carbonyldiimidazol, MeOH, rt, 99%;
b) NaH, MeI, DMF, 0 °C to rt; c) LiBH4, THF, reflux; d) Oxalylchloride, DMSO, NEt3, CH2Cl2, –78 °C to rt; e) triethyl-phosphono acetate, EtOH, NaOMe,
rt, 56% (4 steps); f) Pd/C, H2, MeOH, rt; g) LiBH4, THF, reflux, 73% (2 steps); h) Oxalylchloride, DMSO, NEt3, CH2Cl2, –78 °C to rt; i) triethyl-phosphono
acetate, EtOH, NaOMe, rt, 58% (2 steps); k) Pd/C, H2, MeOH, rt; l) LAH, THF, rt, 97%; m) MeSO2Cl, NEt3, CH2Cl2, rt; n) TFA, CH2Cl2, rt, 73% (2 steps);
o) R3SO2Cl, iPr2NEt, dioxane, rt, 55–76%; p) R3OCOCl, iPr2NEt, dioxane, rt, 70–85%; q) NHR1R2, DMA, rt, 60–75%.

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CHIMIA 2005, 59, No. 3
the benzo[d]isothiazole series for deriva-
tives with various CH2-spacer lengths and
eight different amines is depicted in Fig. 2.
Potent compounds can be identified with
all the different spacer lengths tested, but
there seems to be a slight preference for the
butyl and the hexyl spacer. With these two
chain lengths very active compounds were
found for all of the eight amines tested. Fur-
thermore, the basicity of the amine for com-
pounds can range from pKa values of 6.0 to
10, but a pKa value between 7.8–9.5 seems
to be preferred [25]. Further evaluation of
different amine residues in this series then
focused on the butyl spacers.
S
N
8 different amines: A1 to A8
(CH2)n-Spacer: n = 2 - 7
R1
Spacer
N
O
Br
R2
Those compounds that showed an inhi-
bition of >50% at 100 nM were evaluated
in rat hepatocytes. In this assay both the
cellular activity and the metabolic stability
of the compounds could be assessed. The
test allowed measurement of the potency of
each test substance in reducing cholesterol
production. At the same time the metabolic
stability (residual activity) could be deter-
mined by comparing the reduction of cho-
lesterol production after pre-incubation of
the cells for 24 h with that of co-incubation
of only 2 h [17]. Data for representative
derivatives from both series are depicted
in Table 1. Replacing the benzophenone by
a phenyl-substituted benzo[d]isothiazole
is tolerated as can seen by comparing the
potency of compounds 1 and 9a. Both 9a
and 9b exhibited higher stability as com-
pared to the starting benzophenone 1. The
dioxo-benzo[d]isothiazole 11a was slightly
less potent than the benzo[d]isothiazole
9a but showed similar metabolic stabil-
ity in the hepatocyte assay. For substituted
benzo[d]isothiazole 13a the activity was re-
duced significantly.
In the aminocyclohexane series sev-
eral potent inhibitors were identified. In
the ether linked subseries sulfonamide 18a
and carbamates 19a showed similar stabil-
ity to the benzo[d]isothiazole 9b whereas
the carbamate 19b was less stable. With the
corresponding carbon analogue of 19b, the
carbamate 26a, this property is significantly
improved. A high metabolic stability was
also observed for the sulfonamide 25a.
The most promising compounds from
these new series were evaluated for their
ability to modify lipid parameters in vivo.
For that purpose compounds were given to
hyperlipidemic hamsters as food admix for
14 days and levels of plasma total choles-
terol (TC), LDL-C and TG were measured
and compared to the control group. Data
for two selected aminocyclohexane deriva-
tives, 25a and 26a, are depicted in Table 2 in
comparison to 1. The compounds showed
a significant reduction in all three para-
meters, although dosed significantly lower
Fig. 2. Potency of benzo[d]isothiazole derivatives
Table 1. In vitro activities of selected compounds from the two series
Residual inhibitory
activity after incubation
with rat hepatocytesc
Inhibition of
hOSC
a
IC50
Cpd
R1
R2
n
R3
2h
24h
[nM]
1
6
93%
97%
97%
94%d
n.d.
42%
87%
74%
93%d
n.d.
9a
Me
Et
allyl
HOCH2CH2
allyl
4
2
4
4
1
1
2
3
18
7.8
5%b
17
45
25
11
5
9b
11a
13a
18a
19a
19b
25a
26a
Me
Me
Et
allyl
MeOCH2CH2
HOCH2CH2
allyl
Ph-pCF3
Ph-pCl
94%
91%
95%
98%
99%
77%
79%
25%
90%
86%
Et
Me
Et
Ph-pCF3
Ph-pCF3
Ph-pCF3
HOCH2CH2
allyl
Me
aAll potency measurements were performed in triplicates; b% inhibition of hOSC at 100 nM;
cstability assays at 300 nM in duplicates, dstability assays at 3 μM in duplicates; n.d. not
determined.
Table 2. In vivo activities of selected compounds
dose
[mg/kg/d]
TC
[%]
LDL-C
[%]
TG
[%]
Cpd
1
100
3
–30
–26
–23
–49
–30
–26
–19
–15
–28
25a
26a
6
TC, LDL-C and TG lowering in fat-fed hamsters is expressed as a percent of day 0 (before
compound administration) and corrected with respect to the variation of the untreated group.

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[6] G. Assmann, P. Cullen, H. Schulte, Eur.
9, 639;A. Lenhart, D.J. Reinert, J.D. Aebi,
H. Dehmlow, O.H. Morand, G.E. Schulz,
J. Med. Chem. 2003, 46, 2083.
than 1. As the compounds show similar in
vitro potency this might be attributed to the
improvement of the metabolic stability as
determined in the rat hepatocyte assay.
Heart J. 1998, 19 Suppl A, A2.
[7] A.M. Gotto, Jr., Am. J. Med. 2002, 112,
10S.
[8] P.W. Wilson, Am. J. Hypertens. 1994, 7,
7S.
[21] D. Robinson, R. T. Williams, Biochem. J.
1957, 66, 46P.
[22] J. Aebi, J. Ackermann, H. Dehmlow,
H.-P. Maerki, O. Morand, (F. Hoffmann-
La Roche AG), PCT Int. Appl. 2002,
WO2002036584; J. Ackermann, J. Aebi,
H. Dehmlow, O. Morand, N. Panday, T.
Weller, (F. Hoffmann-La Roche AG), PCT
Int. Appl. 2002, WO2002044149; J. Aebi,
J.Ackermann,A. Chucholowski, H. Dehm-
low, O. Morand, S. Wallbaum, T. Weller, N.
Panday, (F. Hoffmann-La Roche AG), PCT
Int. Appl. 2002, WO2002050041; J. Acker-
mann, J. Aebi, A. Chucholowski, H. Dehm-
low, O. Morand, S. Wallbaum, T. Weller, (F.
Hoffmann-La Roche AG), PCT Int. Appl.
2002, WO 2002020483; J. Ackermann, J.
Aebi,D.Blum,A.Chucholowski,H.Dehm-
low, H.-P. Maerki, O. Morand, R. Trussardi,
E. Von der Mark, S. Wallbaum, T. Weller,
(F. Hoffmann-La Roche AG), PCT Int. Ap-
pl. 2002, WO 2002014267; J. Ackermann,
J. Aebi, A. Chucholowski, H. Dehmlow,
O. Morand, S. Wallbaum, T. Weller, (F.
Hoffmann-La Roche AG), PCT Int. Appl.
2002, WO 2002006189; J. Ackermann, J.
Aebi, H. Dehmlow, G. Hirth, H.-P. Maerki,
O. Morand, (F. Hoffmann-La Roche AG),
PCT Int. Appl. 2003, WO2003053919.
[23] D.M. Fink, J.T. Strupczewski, Tetrahed-
ron Lett. 1993, 34, 6525.
[9] O.H. Morand, J.D. Aebi, H. Dehmlow,
Y.H. Ji, N. Gains, H. Lengsfeld, J. Himber,
J. Lipid Res. 1997, 38, 373.
[10] E.J. Corey, S.C.Virgil, H. Cheng, C.H. Ba-
ker, S.P.T. Matsuda, V. Singh, S. Sarshar,
J. Am. Chem. Soc. 1995, 117, 11819.
[11] T. Schulz-Gasch, M. Stahl, J. Comp.
Chem. 2003, 24, 741.
[12] D.M. Peffley, A.K. Gayen, O.H. Morand,
Biochem. Pharmacol. 1998, 56, 439.
[13] B.A. Janowski, M.J. Grogan, S.A. Jones,
G.B. Wisely, S.A. Kliewer, E.J. Corey,
D.J. Mangelsdorf, Proc. Natl. Acad. Sci.
USA 1999, 96, 266.
[14] K.A.R. Tobin, H.H. Steineger, S. Alberti,
O. Spydevold, J. Auwerx, J.-A. Gustafs-
son, H.I. Nebb, Mol. Endocrinology 2000,
14, 741.
[15] S. Jolidon, A. Polak-Wyss, P.G. Hartman,
P. Guerry, in ‘Molecular Aspects of Che-
motherapy’, Eds. D. Shugar, W. Rode, E.
Borowski, Polish Scientific Publishers
PWN, Warszawa, 1991, pp. 143.
[16] S. Jolidon, A. Polak-Wyss, P.G. Hartman,
P. Guerry, in ‘RecentAdvances in the Che-
mistry ofAnti-infectiveAgents’, Eds. P. H.
Bentley, R. Ponsford, Royal Soc. Chem.,
Cambridge, 1993, pp. 223.
[17] H. Dehmlow, J.D. Aebi, S. Jolidon, Y.-H.
Ji, E.M. Von Mark, J. Himber, O.H. Mo-
rand, J. Med. Chem. 2003, 46, 3354.
[18] R. Thoma, T. Schulz-Gasch, B. D’Arcy, J.
Benz, J. Aebi, H. Dehmlow, M. Hennig,
M. Stihle, A. Ruf, Nature 2004, 432, 118.
[19] K.U. Wendt, A. Lenhart, G.E. Schulz, J.
Mol. Biol. 1999, 286, 175.
Conclusion
Starting from 1 (Ro 48-8071), different
new chemical scaffolds as replacement for
the benzophenone moiety were evaluated.
The individual series could be explored
rapidly by the use of parallel chemistry as
shown for two representative series, leading
to the identification of phenyl-substituted
benzo[d]isothiazole and aminocyclohexane
class which showed improved stability (re-
sidual activity) in rat hepatocytes. The most
promising compounds 25a and 26a from the
aminocyclohexane series showed efficient
lowering of plasma TC, LDL-C, and TG
levels in hyperlipidemic hamsters and were
selected for further profiling.
Acknowledgments
We sincerely thank Daniel Egger, Gisela
Flach, Felix Gruber, Corinne Handschin, Dorian
Heinrich, Barbara Huber, Marie-Paule Imhoff,
Ann Kaiser, Isabelle Kaufmann, Hans-Jakob
Krebs, Anke Kurt, Heidi Stoll and Björn Wagner
for their excellent and dedicated work.
Received: January 6, 2005
[1] http://www.americanheart.org/
downloadable/heart/
1077185395308FS06INT4(ebook).pdf
[2] ATP III Final Report, Circulation 2002,
106, 3143.
[3] R.L. Talbert, Am. J. Manag. Care 2002, 8,
S301.
[4] E. Bruckert, Expert Opin. Investig. Drugs
2003, 12, 325.
[24] A.M. Belostotskii, A. Hassner, Tetrahed-
ron Lett. 1994, 35, 5075.
[25] pKa measurements were performed using
a method described by B.A. Hendriksen,
M.V. Sanchez-Felix, K.Y. Tam, Spectros-
copy Letters 2002, 35, 9.
[20] A. Lenhart, W.A. Weihofen, A.E.W.
Pleschke, G.E. Schulz, Chem. Biol. 2002,
[5] M.B. Clearfield, Expert Opin. Pharmaco-
ther. 2002, 3, 469.