Diphenylpyridylethanamine (DPPE)-based aminoheterocycles as cholesteryl ester transfer protein inhibitors

Article abstract of DOI:10.1016/j.bmcl.2013.12.088

A series of diphenylpyridylethanamine-based inhibitors of cholesteryl ester transfer protein with aminoheterocycles appended onto the N-terminus of the chemotype were explored as urea mimetics. Potent compounds were discovered and were further optimized to improve metabolic stability and PXR transactivation profile.

Full text of DOI:10.1016/j.bmcl.2013.12.088

Bioorganic & Medicinal Chemistry Letters 24 (2014) 860–864
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Diphenylpyridylethanamine (DPPE)-based aminoheterocycles
as cholesteryl ester transfer protein inhibitors
a
a
a
a
a
Yufeng Wang a, , Wu Yang , Heather J. Finlay , Lalgudi S. Harikrishnan , Ji Jiang , Muthoni G. Kamau ,
Katy Van Kirk a, David S. Nirschl b, David S. Taylor c, Alice Ye A. Chen c, Xiaohong Yin c, Paul G. Sleph c,
Richard Z. Yang c, Christine S. Huang d, Leonard P. Adam c, R. Michael Lawrence a, Ruth R. Wexler a,
Mark E. Salvati a
⇑
a Department of Chemistry, Bristol-Myers Squibb, PO Box 4000, Princeton, NJ 08543-4000, USA
b Synthesis & Analysis Technology Team, Bristol-Myers Squibb, PO Box 4000, Princeton, NJ 08543-4000, USA
c Department of Biology, Bristol-Myers Squibb, PO Box 4000, Princeton, NJ 08543-4000, USA
d Department of Preclinical Candidate Optimization, Bristol-Myers Squibb, PO Box 4000, Princeton, NJ 08543-4000, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of diphenylpyridylethanamine-based inhibitors of cholesteryl ester transfer protein with amino-
heterocycles appended onto the N-terminus of the chemotype were explored as urea mimetics. Potent
compounds were discovered and were further optimized to improve metabolic stability and PXR trans-
activation profile.
Received 23 October 2013
Revised 18 December 2013
Accepted 19 December 2013
Available online 6 January 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keyword:
CETP
Atherosclerosis is characterized by the accumulation of lipid
rich plaques within the walls of arteries, and is a key contributor
to coronary heart disease (CHD), cerebrovascular disease and
peripheral arterial disease. These diseases are the leading cause
of mortality in industrialized nations and are a major health con-
cern worldwide.1 Studies have shown that low levels of high-den-
sity lipoprotein cholesterol (HDL-C) in the bloodstream are
associated with a higher risk of CHD, and HDL-C was recognized
as an inverse indicator for risk of developing atherosclerosis.2 Be-
cause of this relationship, the discovery of compounds to increase
HDL-C for the treatment of atherosclerosis has been an active area
for drug discovery research.
benefit with niacin treatment8 (that raised HDL-C to a lesser ex-
tent), has raised concerns about the potential beneficial effects of
raising HDL-C, in general, and by CETP inhibition, in particular.
However, the effects of the relatively weak CETP inhibitor dalcetra-
pib, on HDL-C were small in comparison to the effects of anacetra-
pib and evacetrapib. In addition, anacetrapib and evacetrapib
reduce low-density lipoprotein cholesterol (LDL-C) levels, whereas
dalcetrapib did not. As a result, the potential benefit of potent
pharmacological inhibition of CETP has not been adequately tested
in the clinic. The results of ongoing clinical trials are eagerly antic-
ipated, and the discovery of new CETP inhibitors remains of inter-
est to the cardiovascular field.
Cholesteryl ester transfer protein (CETP) facilitates the transfer
of cholesterol ester from HDL to LDL and VLDL in exchange for tri-
glycerides. Several studies have demonstrated that CETP inhibition
leads to increased HDL-C in animals and humans;3 therefore, phar-
macological inhibition of CETP has been proposed to raise HDL-C
and reduce cardiovascular risk.4 Intensive efforts have been under-
taken to discover efficacious CETP inhibitors,5 and compounds are
currently being evaluated in clinical trials (e.g., anacetrapib6a and
evacetrapib6b). Recently, however, the CETP inhibitor dalcetrapib
(that increases HDL-C by ꢀ30%) failed to demonstrate a cardiovas-
cular benefit.7 This result, coupled with the lack of cardiovascular
Recently, we reported on the discovery of a series of diphenyl-
pyridylethanamine (DPPE) derivatives as CETP inhibitors.9 In that
disclosure, compounds 1 and 2 were identified as active CETP
inhibitors in the scintillation proximity assay (SPA)10 and human
whole plasma assay (WPA),10 and served as lead compounds for
further optimization. Liabilities associated with this class of ureas
generally include poor liver microsomal stability (LMS) and potent
PXR activity in vitro. Biotransformation studies indicated that the
cyclopentyl urea was the principal site of metabolism. Therefore
to improve liver microsomal stability, replacement of the cyclo-
pentyl urea with amides or installation of fluorine onto the cyclo-
pentyl urea to block metabolism were explored and reported.9,10
Described in this manuscript is a concomitant approach (Fig. 1),
whereby aminoheterocycles were appended to the N-terminus of
⇑
Corresponding author. Tel.: +1 609 818 5753.
E-mail address: yufeng.wang@bms.com (Y. Wang).
0960-894X/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.12.088

Y. Wang et al. / Bioorg. Med. Chem. Lett. 24 (2014) 860–864
861
A ring
Cl
N-Terminus
H
Shown in Scheme 1 are the syntheses of N-terminal aminohet-
erocycles prepared as urea mimetics.
Thiourea 5 was synthesized by treating the racemic diphenyl-
pyridylethanamine (DPPE)11 core 4 with isothiocyanate, followed
by hydrolysis with lithium hydroxide. Intermediate 5 was then
Cl
HN
H
N
O
N
R
N
Ar
N
F
coupled with
a-bromoketones 6 to provide the aminothiazoles 7.
F3C
F
Aminotriazole 9 was prepared by treatment of DPPE 4 with ben-
zoyl isothiocyanate, followed by methyl iodide to yield intermedi-
ate 8, which was then treated with hydrazine and silver nitrate.
Aminobenzimidazoles 11, aminobenzoxazoles 12 and amin-
obenzothiazoles 13 were prepared in a similar way by coupling
of the isothiocyanate 10 derived from DPPE 4 to 2-aminothiophe-
nols, 2-aminophenols and 2-aminoanilines, respectively. When
isothiocyanate 10 reacted with 2-azido-1-phenylethanone 15 (pre-
pared from 2-bromo-1-phenylethanone 14), aminoxazole 16 was
obtained. Aminotetrazole posed a synthetic challenge since there
were no previous references of aminotetrazole synthesis on a ter-
tiary carbon reported. We envisioned that aminotetrazole 22 could
be prepared from imine 21 by Strecker reaction with BnMgCl.
While we could not obtain imine 21 by treating 2-methyl-2H-tet-
razol-5-amine 20 with ketone analog of 19 under elevated temper-
ature and/or prolonged reaction time, we were gratified to see
imine 21 could be obtained by heating 2-methyl-2H-tetrazol-
5-amine 20 with imine 19 in xylene at 150 °C with continued heat-
ing for 16 h. Imine 19 was synthesized by lithiation of 17, followed
by reaction with commercially available 18 at À78 °C. This imine-
Strecker route could potentially be applied to the synthesis of other
aminoheterocycles.
A number of different aminoheterocycles were prepared with
racemic core 4 to survey which might hold promise as a suitable
replacement for the terminal cyclopentyl urea (Table 1). Among
the aminoheterocycles tested, aminothiazole 7a, aminobenzimid-
azole 11a and aminobenzothiazole 13 provided the best potency.
Aminobenzoxazole 12 only showed moderate activity, while ami-
notriazole 9, aminooxazole 16 and aminotetrazole 22 were signif-
icantly less active. As a result, further SAR study was focused on the
aminothiazole and aminobenzimidazole series.
R = CF3, 1
R = OCF2CF2H,
2
3
C ring
SPA CETP IC50: 0.02 µM
SPA CETP IC50: 0.007 µM
Plasma CETP IC50: 0.63 µM
microsomal stability
B ring
Plasma CETP IC50: 2.9 µM
microsomal stability
(% remaining @ 10min)
20 (h); 27 (m); 11 (r)
PXR EC60: 1.8 µM
(% remaining @ 10min)
10 (h); 4 (m); 12 (r)
PXR EC60: 0.7 µM
Emax (%CTRL): 65
Emax (%CTRL): 88
Figure 1. N-terminus aminoheterocycles as replacements for cyclopentyl urea.
3 and were explored as urea mimetics. Potent compounds were
discovered with improved metabolic stability and PXR transactiva-
tion profile.
Cl
Cl
R2
R1
Cl
H
N
S
N
NH2
H
N
NH2
Ph
N
N
N
S
a, b
c
Ph
Ph
F3C
F
F3C
F
F3C
F
5
4
7
Ph
N
Cl
N
Cl
N
Ph
H
N
N
H
O
HN
f
d, e
N
SMe
Ph
N
4
Ph
F3C
Cl
F
F3C
F
9
8
HN
Cl
R
NCS
N
HN
g
N
h
N
4
Ph
F
Ph
F
F3C
F3C
10
11
i
Table 1
Cl
N
X
Aminoheterocycles as urea replacements
HN
N
Cl
H
Ph
N
R
N
F3C
F
X = O, 12
X = S, 13
F3C
F
Cl
N
HN
O
O
Ph
O
Ph
Compds
R
CETP SPA IC50
0.4
(lM)
CETP WPA IC50
29.5
(lM)
N
j
k
Br
N3
+
10
Ph
Ph
S
N
7a
F3C
F
14
15
16
H
Ph
N
9
>32
0.2
ND
Cl
n
Cl
Cl
Cl
N
N
N
H
N
N
N
18
N
NH
N
N
N
N
CN
H
N
N
N
N
Br
Ph
l
m
N
F
11a
19.6
N
17
N
O
F3C
F
F3C
F
F3C
F3C
F
19
21
22
12
13
16
2.0
0.5
12
ND
23
N
S
Scheme 1. Synthesis of N-terminal aminoheterocycles. Reagents and conditions:
(a) PhCONCS, DCM, 40 °C, 2 h, 71%; (b) LiOH, MeOH/THF, reflux, 2 h, 78%; (c) 6:
R1COCHR2Br, MeOH, 80 °C, 16 h, 31–78%; (d) PhCONCS, DCM, 100%; (e) MeI, DMF,
63%; (f) H2NNH2, NEt3, AgNO3, ACN, 56 °C, 6 h, 25%; (g) CSCl2, NaHCO3, CHCl3/H2O,
50%; (h) 1,2-dianilines, TEA, EDCI, DCM, 35–85%; (i) X = O, 2-aminophenol, TEA,
EDCI, DCE, 30%; X = S, 2-aminobenzenethiol, TEA, EDCI, DCM, 80%; (j) NaN3, acetone,
H2O, 90%; (k) PPh3, dioxane, 90 °C, 50%; (l) n-BuLi, ether, À78 °C, 100%; (m) 2-
methyl-2H-tetrazol-5-amine 20, xylene, 150 °C, 16 h, 44%; (n) BnMgCl, À78 °C to rt,
DCM, 78%.
N
O
Ph
ND
N
N
N
N
22
11
ND
N

862
Y. Wang et al. / Bioorg. Med. Chem. Lett. 24 (2014) 860–864
A follow-up SAR study on aminothiazoles was conducted and
Cl
Cl
Cl
HN
HN
HN
H
N
the effect of substitutions on the thiazole is summarized in Table 2.
Generally, small hydrophobic groups (Me, Et, CF3, Br) were favored,
with compounds 7a, 7c, 7e, 7g having sub-micromolar potency in
the SPA assay. Compound 7g was the most potent compound in
H
N
H
N
O
N
O
O
N
N
F3C
F
F3C
F
F3C
F
this assay with an IC50 = 0.1
compound 7d resulted in about a 10 fold loss in SPA potency when
compared to its ethyl counterpart 7c (7.5 vs 0.7 M). Polar/hydro-
lM. The bulky t-butyl substituted
1 (S)
24 (R)
23 (Rac)
SPA IC50: 0.02 µM
WPA IC50: 2.9 µM
SPA IC50: 1.2 µM
WPA IC50: 71.9 µM
SPA IC50: 0.03 µM
WPA IC50: 5.5 µM
l
philic groups such as CO2Me were not tolerated. In comparing the
5-Me compound 7a to the methyl ester compound 7h, an 80 fold
Cl
S
Cl
S
Cl
S
HN
HN
N
N
HN
loss in SPA potency (32 vs 0.4
SAR to disubstituted thiazoles, we observed that 4,5-disubstituted
thiazole 7a was more potent than compound 7b (0.4 vs 1.1 M)
and that 7g was more potent than mono-CF3 compound 7f (0.1
vs 1.2 M). Cyclohexyl compound 7e in which positions 4 and 5
lM) was observed. Extending the
N
N
N
N
l
F3C
F
F3C
F
F3C
F
7a (Rac)
7j (S)
7i (R)
l
SPA IC50: 0.4 µM
SPA IC50: 12.2 µM
SPA IC50: 0.04 µM
WPA IC50: 17.3 µM
were linked to form a hydrophobic 6-carbon ring, further improved
WPA IC50: 29.5 µM
WPA IC50: ND
SPA potency over its 4,5-dimethyl counterpart 7a by two fold (0.2
vs 0.4 lM).
Cl
S
Cl
S
Cl
S
HN
HN
N
N
HN
Initial SAR studies with racemic DPPE amine enabled us to
quickly identify thiazoles to further optimize. To identify the ste-
reochemical preference of the aminoheterocycle series, two pairs
of enantiomers, (7i/7j) of 7a and (7k/7l) of 7e, were prepared from
the chiral amines and tested. CETP inhibitory activity was found to
reside primarily in one enantiomer. Surprisingly the stereochemi-
cal preference of the aminoheterocycles was R- in contrast to the
corresponding urea/amide analogs where the more active enantio-
mer configuration was S- (Fig. 2). The absolute stereochemistry of
the quaternary center was determined by 1H NMR analysis of the
corresponding Mosher’s amide.12 The reversal of stereochemical
preference was also consistent for other aminoheterocycles
surveyed.13
N
N
N
N
F3C
F
F3C
F
F3C
F
7e (Rac)
7l (S)
7k (R)
SPA IC50: 0.2 µM
SPA IC50: 10.8 µM
SPA IC50: 0.04 µM
WPA IC50: 8.2 µM
WPA IC50: 20.2 µM
WPA IC50: ND
Figure 2. Reversal of stereochemical preference between aminoheterocycles and
urea.
Table 3
PK/PD comparison of urea 1 and aminothiazole 7k
For head-to-head comparison, aminothiazole 7k and urea 1
were selected for PK/PD study in hCETP/apo B-100 transgenic mice,
both dosed orally at 30 mpk. As shown in Table 3, compound 7k
achieved slightly better exposure and higher plasma concentra-
tions at 2 and 4 h than urea 1, likely due to its slightly improved
liver microsomal stability in mice. However, because of weaker
WPA potency, 7k showed a lower PD effect (26% inhibition vs
56% inhibition at 8 h). Further improvement in potency was
needed for the aminothiazole series.
H
N
Cl
Cl
N
S
H
N
H
N
N
O
N
7k
1
F3C
F
F3C
F
Parallel SAR studies developed in our program on the B-ring
identified a further optimized 3,5-disubstituted phenyl fragment
which was subsequently utilized for the optimization of fluori-
nated ureas.9,10 Specifically, it was observed that addition of a
tetrafluorinated ethoxy group demonstrated a significant enhance-
ment in WPA potency (i.e., 2 vs 1). The DPPE with a tetrafluorinated
Compd 1
Compd 7k
SPA IC50
WPA IC50
LM stability (%remaining
(
l
(lM)
M)
0.02
2.9
0.04
8.2
20(h), 27(m), 11(r) 73(h), 33(m), 56(r)
@10 min)
⁄AUC (nM h)
5713
8179
2531, 1241, 142
26%
Plasma Conc. (nM) @2, 4, 8 ha
Inhibition of CETP activity@ 8 ha
1754, 1012, nab
56%
a
30 mpk PO dose in hCETP/apo B-100 transgenic mice.
na = Not available.
Table 2
b
SAR of substituted aminothiazoles against human CETP
R2
5
Cl
S
HN
R1
N
4
N
ethoxy group was then utilized to carry out SAR studies on the
terminal aminoheterocyclic series. Summarized in Tables 4 and 5
are potency and profiling data of selected aminothiazoles and
aminobenzimidazoles with incorporation of the optimized B-ring.
In Table 4, aminothiazoles combined with the tetrafluorinated eth-
oxy B ring in general achieved improved potency compared with
the CF3 substituted B ring (7n vs 7g, 7o vs 7k). Although 7i and
7m had the same SPA potency, 7m was more potent in the WPA
assay. Compared to urea lead 2, aminothiazole compounds in
Table 4 in general were 3–30 fold less potent. However, 7n, 7p
and 7q all showed improvements on PXR, CYP and liver micro-
somal stability over urea lead 2.
F3C
F
7
Compds
R1, R2
SPA IC50 (lM)
7a
7b
7c
7d
7e
7f
Me, Me
H, Me
Et, H
tBu, H
–CH2CH2CH2CH2–
CF3, H
0.4
1.1
0.7
7.5
0.2
1.2
0.1
32
7g
7h
CF3, Br
Me, CO2Me
Aminoimidazoles in Table 5 demonstrated similar improve-
ments on PXR, CYP and liver microsomal stability, compared to

Y. Wang et al. / Bioorg. Med. Chem. Lett. 24 (2014) 860–864
863
Table 4
SAR and profiling of aminothiazoles with optimized B-ring
R2
R1
Cl
S
N
H
N
N
HF2CF2CO
F
7
Compds
N-terminus
R1, R2
SPA
IC50
WPA
PXRa
EC60
CYP IC50
(
l
M)
LM stability
(%remaining @10 min) (h, m, r)
(
lM)
IC50
(
lM)
(lM)
1A2, 2C9, 2C19, 2D6, 3A4 (BZRes), 3A4 (BFC)
(Emax% CTRL)
2
Urea
Me, Me
CF3, Br
–CH2CH2CH2CH2–
CF3, H
0.007
0.04
0.04
0.02
0.22
0.02
0.63
5.5
6.5
4.2
14.8
3.2
0.7 (88)
na
>5.6 (37)
na
>17 (45)
>5.6 (44)
40, 4.4, 17, 15, 3.6, 8.8
na
All >40
na
40, 40, 13, 40, 40, 40
All >40
11, 11, 26
na
100, 100, 95
na
98, 78, 83
82, 59, 55
7m
7n
7o
7p
7q
CF3, Me
a
Compounds were tested at 10 concentrations (0.0025–50 lM) using 10 lM rifampicin as positive control. PXR activity of compounds is expressed as % of Control Activity
(% CTRL), where control activity is the response observed with 10
lM rifampicin.
Table 5
SAR and profiling of aminobenzimidazoles
7
H
N
Cl
6
H
N
R
N
N
5
4
HF2CF2CO
F
11
Compds N-terminus R
SPA
IC50
WPA
IC50
(lM)
PXRa EC60
CTRL)
(lM) (Emax
%
CYP IC50
(
l
M)
LM stability
(%remaining @10 min) (h, m,
r)
1A2, 2C9, 2C19, 2D6, 3A4(BZRes),
3A4(BFC)
(lM)
2
Urea
R = H
R = 5-F
R = 5,7-diF
0.007
0.09
0.05
0.04
0.63
15
9.5
6.4
0.7 (88)
>17 (70)
>17 (56)
>5.6 (25)
40, 4.4, 17, 15, 3.6, 8.8
40, 19, 3, 40, 13, 40
40, 40, 2, 29, 40, 32
40, 15, 3, 40, 19, 24
11, 11, 26
na
56, 62, 95
68, 72, 100
11b
11c
11d
a
Compounds were tested at 10 concentrations (0.0025–50
lM) using 10
lM rifampicin as positive control. PXR activity of compounds is expressed as % of Control Activity
(% CTRL), where control activity is the response observed with 10
lM rifampicin.
H. J.; Gillespie, C.; Hailpern, S. M.; Heit, J. A.; Howard, V. J.; Huffman, M. D.;
Kissela, B. M.; Kittner, S. J.; Lackland, D. T.; Lichtman, J. H.; Lisabeth, L. D.;
Magid, D.; Marcus, G. M.; Marelli, A.; Matchar, D. B.; McGuire, D. K.; Mohler, E.
R.; Moy, C. S.; Mussolino, M. E.; Nichol, G.; Paynter, N. P.; Schreiner, P. J.; Sorlie,
P. D.; Stein, J.; Turan, T. N.; Virani, S. S.; Wong, N. D.; Woo, D.; Turner, M. B.
Circulation 2013, 127, e6.
urea lead 2. However, similar to the observation in the aminothia-
zole series, compared to lead 2, compounds 11(b–d) lost around
5–10 fold in potency in the SPA and WPA assays.
In conclusion, N-terminus aminoheterocycles were synthesized
as cyclopentyl urea replacements in the CETP program. Of the
aminoheterocycles surveyed, aminothiazole and aminobenzimid-
azole provided the best in vitro potency. SAR studies of these
two series identified compounds with comparable SPA potency
to the urea, and with improved metabolic stability, PXR transacti-
vation and CYP inhibition profiles. Further efforts in the DPPE ser-
ies to identify novel compounds with improvements on WPA
potency will be reported in due course.
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We are grateful to Dr. William Rick Ewing for reviewing this
manuscript. We are also grateful to Dr. Tatyana A. Zvyaga, Monique
N. Anthony, Jeremy Hurley, Cheryl A. Ferraro and Marianne Vath
for generating PXR, CYP inhibition and microsomal stability data.
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