Novel tetrahydrochinoline derived CETP inhibitors

Article abstract of DOI:10.1016/j.bmcl.2010.01.071

In the course of our efforts to identify orally active cholesteryl ester transfer protein (CETP) inhibitors, we have continued to explore tetrahydrochinoline derivatives. Based on BAY 19-4789 structural modifications led to the discovery of novel cycloalkyl substituted compounds. Thus, example 11b is a highly potent CETP inhibitor both in vitro and in vivo in transgenic mice with favourable pharmacokinetic properties for clinical development.

Full text of DOI:10.1016/j.bmcl.2010.01.071

Bioorganic & Medicinal Chemistry Letters 20 (2010) 1740–1743
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Novel tetrahydrochinoline derived CETP inhibitors
*
Carsten Schmeck , Heike Gielen-Haertwig, Alexandros Vakalopoulos, Hilmar Bischoff, Volkhart Li,
Gabriele Wirtz, Olaf Weber
Bayer HealthCare AG, Bayer Schering Pharma, Global Drug Discovery, D-42096 Wuppertal, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
In the course of our efforts to identify orally active cholesteryl ester transfer protein (CETP) inhibitors, we
have continued to explore tetrahydrochinoline derivatives. Based on BAY 19-4789 structural modifica-
tions led to the discovery of novel cycloalkyl substituted compounds. Thus, example 11b is a highly
potent CETP inhibitor both in vitro and in vivo in transgenic mice with favourable pharmacokinetic prop-
erties for clinical development.
Received 17 December 2009
Revised 5 January 2010
Accepted 6 January 2010
Available online 21 January 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Tetrahydrochinolines
CETP inhibitor
HDL
Torcetrapib
Cardiovascular disease is the most common cause for mortality
and morbidity in the developed world and it is estimated that mor-
tality from cardiovascular diseases will have increased worldwide
by 90% by the year 2020 when compared with the situation in
1990.1 Despite the fact that a large portion of cardiovascular events
cannot be prevented by lowering of low-density lipoprotein cho-
lesterol (LDL-C), guidelines for the prevention of cardiovascular
disease still focus on the management of LDL-C.2,3
We have searched for orally active CETP inhibitors suitable for
clinical development.10 Our first compound investigated in
humans, BAY 19-4789 (4) was discontinued in early clinical devel-
opment due to unexpected toxicological findings in a 13 week re-
peat dose toxicology study in dogs.
For a second candidate, BAY 38-1315 (5), preclinical develop-
ment was stopped because of unfavourable pharmacokinetic prop-
erties (see Fig. 2).
Several epidemiological studies clearly show that a low level of
high density lipoprotein cholesterol (HDL-C) is a strong and inde-
pendent risk factor for the development of CHD and HDL has been
proposed to have potential atheroprotective effects.4
Inhibition of cholesteryl ester transfer protein (CETP) might be a
powerful tool for increasing HDL-C, decreasing LDL-C and very
low-density lipoprotein (VLDL-C) thus reducing the development
of atherosclerosis.5
CF3
CF3
CF3
CF3
O
O
O
O
N
N
N
CF3
CF3
O
NH
S
O
The recent failure of torcetrapib (1) in phase III studies chal-
lenged the future perspectives of CETP inhibitors as potential ther-
apeutic agents.6 Since compound-specific and off-target effects of
torcetrapib, such as raising blood pressure and aldosterone were
most likely causative for an increase in cardiovascular events and
mortality, it has been suggested to continue studying other CETP
inhibitors for their potential to reduce cardiovascular risk.7 Cur-
rently the most advanced compounds dalcetrapib, JTT-705, (3)
and anacetrapib (2), which have not been reported to have the
off-target effects of torcetrapib, are in phase III clinical trials8,9
(see Fig. 1).
F
O
O
O
Torcetrapib
1
Anacetrapib
2
Dalcetrapib 3
Figure 1. Past and present CETP inhibitors in clinical development.
F
F
OH
F
F
OH
CF3
N
CF3
BAY 19-4789
4
BAY 38-1315 5
* Corresponding author. Tel.: +49 202 36 3936; fax: +49 202 36 4061.
E-mail address: carsten.schmeck@bayerhealthcare.com (C. Schmeck).
Figure 2. Tetrahydrochinoline and tetrahydronaphtaline derived CETP inhibitors.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.01.071

C. Schmeck et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1740–1743
1741
Table 1
In seeking a backup compound we were interested in replacing
IC50 data from CETP fluorescence assay for compounds 1, 4, 5 and 7a–r
the 4-fluorophenyl substituent present both in 4 and 5 without
further increasing lipophilicity. Therefore we continued our SAR
exploration in the tetrahydrochinoline series only. For the intro-
duction of new ‘head’ groups we were following a synthetic route
using an unsymmetrical Hantzsch-dihydropyrididine synthesis as
the key step, followed by an oxidation with DDQ to the pyridines
6 (Scheme 1). Diketone 6 undergoes a completely regioselective
CBS-type reduction11 using (1R, 2S)-1-aminoindan-2-ol as chiral
inductor with high enantioselectivity (>95% ee) to provide the alco-
hols 7. Yields for the dihydropyridine formation employing ali-
phatic aldehydes are generally lower compared to aromatic
aldehydes.10a However, taking into account the high complexity
of the diketones 6 which are being assembled in two steps, a low
Compds
R1
=
R2
=
X =
IC50 (nM)
clog P13
1
18
7.55
7.95
8.63
7.07
7.43
8.66
7.30
7.47
6.98
8.10
7.94
8.03
7.86
8.66
8.50
4
31
5
24
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
Et
nPr
nPent
iPr
iPr
cPent
cPent
cPent
cPent
cPent
cPent
cPent
cPent
iPr
Dimethyl
Spirocyclobutyl
Dimethyl
Dimethyl
Spirocyclobutyl
Dimethyl
Dimethyl
Spirocyclobutyl
Dimethyl
Spirocyclobutyl
Dimethyl
Spirocyclobutyl
4500
600
2000
600
300
3000
90
70
70
33
60
cPr
cPent
cPent
cHex
cHex
cHex
cHex
iPr
cPent
cPent
yielding sequence is acceptable in order for
assessment.
a rapid SAR
55
Several SAR trends are apparent comparing the analogues
shown in Table 1. CETP inhibition was determined using a CETP
fluorescence assay.12a
7m
7n
cPent
cPent
Dimethyl
Dimethyl
2000
3000
8.00
6.78
F
F
F
For substituents at R1 a rather steep SAR can be observed with
respect to steric bulk and polarity. Branched alkyl substituents
are obviously more potent than alkyl chains.
Cl
7o
7p
cPent
cPent
Dimethyl
Dimethyl
15,000
6.60
6.08
O
OEt
>20,000
Cbz
N
7q
7r
cPent
cPent
Dimethyl
Dimethyl
500
9.36
6.24
O
R1
O
O
O
O
R1
H
N
a
+
+
R2
>20,000
CF3
NH2
O
CF3
R2
N
H
X
X
O
X
b
7s
7t
N
cPent
cPent
Dimethyl
Dimethyl
15,000
4000
7.07
6.24
O
R1 OH
O
R1
N
c
CF3
R2
N
X
CF3
R2
N
7
6
Thus, the cyclopentyl and cyclohexyl substituents in com-
pounds (7g–l) represent the optimal combination of lipophilicity
and steric requirements. Attempts to increase polarity by introduc-
ing an amino functionality resulted in a loss of activity. The pyrolli-
dine derivative (7t) and the Cbz-protected piperidine (7q) still
show some activity while the more basic amines (7r, 7s) are
inactive.
H
Cbz
N
N
O
OH
O
OH
e
CF3
CF3
CF3
N
CF3
N
In accordance to previously observed SAR,10a the spirocyclobu-
tyl substituent on the saturated ring of the tetrahydrochinoline
adds additional potency compared to the dimethyl substitution
pattern. A further increase in CETP inhibition should be achievable
by replacing the sp2 keto functionality present in 7i–l by connect-
ing the pyridine moiety and the 4-CF3-phenyl group via a sp3 car-
bon (see Fig. 3).
The hydroxy-ketones 7i–l were reduced with moderate diaste-
reoselectivities (60–70% de) using DIBAL in toluene at low temper-
atures to give the desired trans-dihydroxy derivatives 8a–b
(Scheme 2).
7 r
7 q
N
Cl
O
OH
O
OH
d
N
CF3
N
7 s
7 o
O O
O
N
OH
O
OH
Regioselective protection of the sterically less hindered hydro-
xyl group was achieved with t-butyldimethylsilyl-chloride in
refluxing acetonitrile to give 10a–b. Alternatively, the hydroxy-ke-
tones were first protected using t-butyldimethylsilyltriflate in tol-
f
N
CF3
N
7 t
7 p
Scheme 1. Synthesis of alcohols 7. Reagents and conditions: (a) 1.2 equiv enamine,
2 equiv TFA, 1 equiv diketone, rt, 10 min, then 1.5 equiv R1 CHO, rt, 18 h, 5–55%; (b)
1.1 equiv DDQ, CH2Cl2, rt, 1 h, 20–95%; (c) 0.15 equiv (1R,2S)-1-aminoindan-2-ol,
4 equiv N,N-diethylaniline–borane (1:1), THF, rt, 15 min, then 6, 0 °C to rt, 18 h, 58–
95%; (d) 4 equiv piperidine, 2 equiv N-ethyldiisopropylamin, DMF, 110 °C, 18 h,
80%; (e) Pd/C, H2 1 bar, THF/MeOH 1:1, 16 h, 68% and (f) (i) 10 equiv 10% NaOH,
EtOH, 18 h, 95%; (ii) 2 equiv DPPA, 2 equiv NEt3, 2 equiv H2O, toluene, 90 °C, 18 h,
74% and (iii) 2.5 equiv NaH, THF, 30 min then 1.1 equiv 1,4-dibrombutane, THF,
18 h, 22%.
R1 = H, OH, F
R1
R2
OH
R2 =
X =
,
CF3
N
X
,
Figure 3. Matrix of 4-cyclohexyl-tetrahydrochinoline CETP inhibitors.

1742
C. Schmeck et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1740–1743
Table 3
IC50 data from CETP fluorescence assay in human plasma and from CETP SPA assay for
compounds 11a–d and 12
OH
R2
OH
O
OH
a
Human plasma assay12b
IC50 (nM)
SPA assay12c
IC50 (nM)
R2
Compds
CF3
CF3
CF3
CF3
N
X
CF3
N
X
7 i-l
8 a, b
1
20
75
50
70
60
3
23
7
33
62
n.a.
11a
11b
11c
11d
12
c
b
300
O
OSiMe2tBu
X
OH
R2
OSiMe2tBu
X
d
R2
CF3
N
N
9
10
duction of the fluorine atom in 11a–d increased both lipophilicity
and CETP inhibitory activity. Activity as well as lipophilicity of the
defluorinated compound 12 is in the range of 11a–d (Table 2).
Additional in vitro tests were performed with compounds 11a–
d and 12 showing the best overall in vitro profile for compound
11b (Table 3).
The pharmacokinetic profile of 11b was assessed in mice, rats
and dogs revealing good plasma half-lives (t1/2 = 5.0, 7.2 and
8.6 h, respectively) and oral bioavailability (F = 44% in rats and
74% in dogs).
In conclusion, we successfully modified the structure of our pre-
vious development compounds 4 and 5 by replacing the pF-phenyl
moiety with a cyclohexyl group in the 4-position. With its good
overall in vitro profile and the favourable pharmacokinetic profile,
11b improved the lipoprotein profile in human CETP-transgenic
mice by increasing HDL-cholesterol and lowering serum triglycer-
ides dose dependently.15 Consequently, 11b was selected for
advancement as a clinical candidate.
g
e
OH
OH
F
OH
X
R2
R2
CF3
N
X
N
11 a-d
8 c, d
f
OH
R2
N
X
12
Scheme 2. Synthesis of alcohols 8–12. Reagents and conditions: (a) 5 equiv DIBAL,
toluene, À78 °C to rt, 18 h, 70–80%; (b) 7 equiv TBDMSCl, 2.5 equiv DMAP, 6 equiv
NEt3, acetonitrile, rt, 18 h, 79%; (c) 2 equiv TBDMSOTf, 4 equiv 2,6-dimethylpyri-
dine, toluene, À15 to 0 °C, 2 h, 78–99%; (d) 5 equiv DIBAL, toluene, À50 °C to rt, 3 h,
30–40%; (e) (i) 1.5 equiv DAST, CH2Cl2, , À78 °C to rt, 2 h, 82–95%; (ii) 2.5 equiv
TBAF, THF, 0 °C to rt, 18 h, 65–91%; (f) 7 equiv DIBAL, toluene, À20 to 0 °C, 4 h, 80%
and (g) 2.5 equiv TBAF, THF, 0 °C to rt, 18 h, 78–95%.
Acknowledgements
We thank Dr. Rolf Grosser and his lab for HPLC support and Dr.
Holger Paulsen and his lab for synthesis of starting materials and
their up scaling efforts. We thank Dr. Delf Schmidt for assay
development.
uene at low temperatures followed by a non selective reduction
with DIBAL in toluene to afford 10c–d. Enantioselective fluorina-
tion with diethylaminosulfur trifluoride (DAST) in dichlorometh-
ane at low temperatures occurred with complete retention of the
configuration. In contrast to the usual SN2 pathway of DAST-fluori-
nations the reaction proceeds with retention of configuration at
this sterically highly encumbered site. Similar fluorinations follow-
ing a SNi-mechanism have been reported in the literature.14 Re-
moval of the protecting group proceeded cleanly with TBAF in
THF yielding 8c–d and 11a–d. Reductive defluorination of 11b with
a high excess of DIBAL in toluene afforded 12 (Scheme 2).
References and notes
1. Yusuf, S.; Reddy, S.; Ounpuu, S.; Anand, S. Circulation 2001, 104, 2746.
2. Third Report of the National Cholesterol Education Program (NCEP) Expert
Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in
Adults 1. (Adult Treatment Panel III) final report Circulation 2002, 106, 3143–
3421.
3. Grundy, S. M.; Cleeman, J. I.; Merz, C. N.; Brewer, H. B.; Clark, L. T.;
Hunninghake, D. B.; Pasternak, R. C.; Smith, S. C.; Stone, N. J. Circulation 2004,
110, 227 [Erratum: Circulation 2004, 110, 763].
4. (a) Gordon, T.; Castelli, W. P.; Hjortland, M. C.; Kannel, W. B.; Dawber, T. R. Curr.
Med. Res. Opin. 2004, 20, 1253–1268. and references cited therein; (b) Assmann,
G.; Schulte, H.; von Eckardstein, A.; Huang, Y. Atherosclerosis 1996, 124, S11–
S20; (c) Linsel-Nitschke, P.; Tall, A. R. Nat. Rev. Drug. Disc. 2005, 4, 193
[Erratum: Nat. Rev. Drug. Disc. 2005, 4, 648].
5. De Grooth, G. J.; Klerkx, A. H. E. M.; Stroes, E. S. G.; Stalenhoef, A. F. H.;
Kastelein, J. J. P.; Kuivenhoven, J. A. J. Lipid Res. 2004, 45, 1964–1974.
6. (a) Barter, P. J.; Caulfield, M.; Eriksson, M.; Grundy, S. M.; Kastelein, J. J. P.;
Komajda, M.; Lopez-Sendon, J.; Mosca, L.; Tardif, J.; Waters, D. D.; Shear, C. L.;
Revkin, J. H.; Buhr, K. A.; Fisher, M. R.; Tall, A. R.; Brewer, B. N. Eng. J. Med. 2007,
357, 2109; (b) Nissen, S. E.; Tardif, J. C.; Nicholls, S. J.; Revkin, J. H.; Shear, C. L.;
Duggan, W. T.; Ruzyllo, W.; Bachinsky, W. B.; Lasala, G. P.; Tuzcu, E. M. N. Eng. J.
Med. 2007, 356, 1304.
The increase in polarity of the trans-dihydroxy compounds 8 led
to a slight loss in activity compared to 7. On the other hand intro-
Table 2
IC50 data from CETP fluorescence assay for compounds 8a–d, 11a–d and 12
Compds
R2
=
X =
IC50 (nM)
clog P13
7. (a) Joy, T.; Hegele, R. A. Curr. Opin. Cardiol. 2009, 24, 364; (b) Neeli, H.; Rader, D.
J. Cardiol. Clin. 2008, 26, 537.
8a
8b
8c
8d
11a
11b
11c
11d
12
iPr
cPent
iPr
cPent
iPr
cPent
iPr
Dimethyl
Dimethyl
Spirocyclobutyl
Spirocyclobutyl
Dimethyl
80
100
70
100
30
25
17
22
39
6.76
7.39
6.59
7.23
8.14
8.77
7.97
8.61
9.15
8. (a) De Grooth, G. J.; Kuivenhoven, J. A.; Stalenhoef, A. F.; De Graaf, J.;
Zwinderman, A. H.; Posma, J. L.; Van Tol, A.; Kastelein, J. J. P. Circulation 2002,
105, 2159; (b) Stein, E. A.; Stroes, E. S. G.; Steiner, G.; Buckley, B. M.; Phild, D.;
Capponi, A. M.; Burgess, T.; Niesor, E. J.; Kallend, D.; Kastelein, J. J. P. Am. J.
Cardiol. 2009, 104, 82.
9. Cannon, C. P.; Dansky, H. M.; Davidson, M.; Gotto, A. M., Jr.; Brinton, E. A.;
Gould, A. L.; Stepanavage, M.; Liu, S. X.; Shah, S.; Rubino, J.; Gibbons, P.;
Hermanowski-Vosatka, A.; Binkowitz, B.; Mitchel, Y.; Barter, P. Am. Heart J.
2009, 158, 513.
Dimethyl
Spirocyclobutyl
Spirocyclobutyl
Dimethyl
cPent
cPent

C. Schmeck et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1740–1743
1743
10. (a) Paulsen, H.; Schmeck, C.; Brandes, A.; Schmidt, G.; Stoltefuss, J.; Wirtz, S. N.;
Lögers, M.; Naab, P.; Bremm, K.-D.; Bischoff, H.; Schmidt, D.; Zaiss, S.; Antons, S.
Chimia 2004, 58, 123; (b) Paulsen, H.; Antons, S.; Brandes, A.; Lögers, M.;
Müller, S. N.; Naab, P.; Schmeck, C.; Schneider, S.; Stoltefuss, J. Angew. Chem.,
Int. Ed. 1999, 38, 3373; (c) Brückner, D.; Hafner, F.-T.; Li, V.; Schmeck, C.; Telser,
J.; Vakalopoulos, A.; Wirtz, G. Bioorg. Med. Chem. Lett. 2005, 15, 3611.
11. (a) Di Simone, B.; Savoia, D.; Tagliavini, E.; Umani-Ronchi, A. Tetrahedron:
Asymmetry 1995, 6, 301; (b) Ghosh, A. K.; Fidanze, S.; Senanayake, C. H.
Synthesis 1998, 937.
12. a To assess CETP activity an microemulsion based assay according to Bisgaier
et al., (J. Lipid Res. 1993, 34, 1625–1634) was used with the following
modification: (1) Donor liposomes were prepared applying 1 mg Cholesteryl
4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-dodecanoate
(cholesteryl BODIPYÒ FL C12, from Molecular Probes), 5.35 mg triolein (Sigma–
Aldrich) and 6.67 mg POPC (Sigma–Aldrich), respectively, dissolved in a total
intensity (excitation 485 nm, emission 535 nm) is proportional to the
cholesterol ester transfer. The inhibition of the transfer is followed in
comparison with a DMSO control.; b To assess CETP activity in the presence
of human plasma 6
lL (12% v/v) of donor liposomes and 1
lL (2% v/v) of a
solution of the substance to be tested in DMSO are added to 42
lL (86% v/v) of
human plasma (Sigma P 9523). The mixture is incubated at 37 °C for 24 h. The
change in the fluorescence at 510/520 nm is a measure of the cholesterol ester
transfer. The inhibition of the transfer is followed in comparison with a DMSO
control.; c To assess CETP activity a scintillation proximity assay the transfer of
3H-cholesterol ester from human HD lipoproteins to biotinylated LD
lipoproteins is measured. In the test batch, 10
(ꢀ50,000 cpm) are incubated at 37 °C for 18 h with 10
(Amersham) in 50 nM Hepes/0.15 M NaCl/0.1% bovine serum albumin/0.05%
NaN3 pH 7.4 containing 10 L of CETP (1 mg/ml) and 3 L of a solution of the
substance to be tested (dissolved in 10% DMSO/1% BSA). 200 L of the SPA-
l
L of HDL-3H-cholesterol ester
of biotin-LDL
l
L
l
l
l
volume of 600
l
L dioxane and were slowly injected into 63 mL buffer (50 mM
streptavidin bead solution (TRKQ 7005) are then added, incubated further with
shaking for 1 h and then measured in a scintillation counter. Corresponding
incubations with 10 lL of buffer, 10 lL of CETP serve as controls.
Tris/HCl pH 7.3, 150 mM NaCl, 2 mM EDTA) in a water bath sonicator. This
suspension is then sonicated with 50 W (Branson Sonifier 450 with a cup-horn
resonator) for 30 min under a nitrogen atmosphere at room temperature. (2)
Acceptor liposomes were prepared in the same manner as donor liposomes
using 86 mg cholesteryl-oleate, 20 mg triolein und 100 mg POPC dissolved in
1.2 mL dioxane and injected into 114 mL buffer. (3) In a total test volume of
13. For clog P-calculations the fragment summation method CLOGP (version 4.3
with version 23 of its associated fragment database, as implemented in Sybyl
version 8.0, Tripos Inc.) has been used.
14. (a) Mori, Y.; Morishima, N. Bull. Chem. Soc. Jpn. 1994, 67, 3377; (b) Castillon, S.;
Dessinges, A.; Faghih, R.; Lukacs, G.; Olesker, A.; Thang, T. T. J. Org. Chem. 1985,
50, 4913.
100
4 h with 50
human plasma) and 48
buffer and 2 volumes acceptor, respectively). The increase of the fluorescence
l
L test compounds dissolved in DMSO (2
L of a CETP containing sample (1–3
L of a liposome emulsion (1 volume donor, 1 volume
l
L) were incubated at 37 °C for
l
l
g CETP, enriched from
l
15. Data published in part in WO2006/063828.