Discovery of dehydro-oxopiperazine acetamides as novel bradykinin B1 receptor antagonists with enhanced in vitro potency

Article abstract of DOI:10.1016/j.bmcl.2011.11.112

In a series of bradykinin B1 antagonists, we discovered that replacement of oxopiperazine acetamides with dehydro-oxopiperazine acetamides provided compounds with enhanced activity against the B1 receptor. The synthesis and SAR leading to potent analogs w

Full text of DOI:10.1016/j.bmcl.2011.11.112

Bioorganic & Medicinal Chemistry Letters 22 (2012) 1061–1067
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of dehydro-oxopiperazine acetamides as novel bradykinin B1
receptor antagonists with enhanced in vitro potency
Wenyuan Qian a, , Jian Jeffrey Chen a, Jason Human a, Toshihiro Aya a, Jiawang Zhu a, Kaustav Biswas a,
⇑
Tanya Peterkin a, Randall W. Hungate a, Leyla Arik b, Eileen Johnson b, Gondi Kumar c, Smriti Joseph d,
Janan Jona d, Hong-Xun Guo e, Zufan Wu e
a Department of Chemistry Research and Discovery, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States
b Department of Neuroscience, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States
c Department of Pharmacokinetics & Drug Metabolism, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States
d Department of Pharmaceutical Science, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States
e Department of Analytical Research and Development, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
In a series of bradykinin B1 antagonists, we discovered that replacement of oxopiperazine acetamides
with dehydro-oxopiperazine acetamides provided compounds with enhanced activity against the B1
receptor. The synthesis and SAR leading to potent analogs with reduced molecular weight will be
discussed.
Received 24 October 2011
Revised 23 November 2011
Accepted 28 November 2011
Available online 8 December 2011
Ó 2011 Published by Elsevier Ltd.
Keywords:
Bradykinin B1
Antagonist
Pain
Inflammation
Dehydro-oxopiperazine
Kinins are peptidic hormones that are released at sites of tissue
injury and produce pain and inflammation via activation of consti-
tutively expressed bradykinin B2 and inducible bradykinin B1
receptors.1–3 In the last decade there has been intense interest in
identifying orally active Bradykinin B1 receptor antagonists for
the treatment of inflammation and pain.4–13 We recently reported
that 2-((R)-3-oxo-1-tosylpiperazin-2-yl)-N-((R)-6-(piperidin-1-yl-
methyl)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide (1a, Fig. 1)
was a highly potent B1 antagonist with improved metabolic stabil-
ity and reduced protein binding compared to our early generation
of B1 antagonists.14 During its synthesis we isolated benzyl dehy-
dro-oxopiperazine acetate as an intermediate which was reduced
directly to the desired oxopiperazine acetic acid. Elsewhere, we
reported that a related series of compounds represented by dihy-
droquinoxalinone acetamides such as 3 (Fig. 1) were also highly
active B1 antagonists.13 Because of the structural similarity be-
tween 1a and 3 we postulated that 2a, as the truncated version
of 3, should also be an active B1 antagonist. In the literature
dehydro-oxopiperazines have not been studied extensively. They
were used as synthetic intermediates to oxopiperazines for a
number of factor Xa inhibitors.15 In this report we demonstrate
that dehydro-oxopiperazines such as 2a are stable chemical
entities that provide enhanced activity against B1 receptor.
Compound 2a was synthesized according to Scheme 1, modified
from the route for the synthesis of 1.14 (R)-2-Amino-4-tert-butoxy-
4-oxobutanoic acid 4 was sulfonylated and then coupled with
2,2-dimethoxyethanamine to give the amide 6. Acid catalyzed
cyclization in heated dioxane gave the dehydro-oxopiperazine 7.
The tert-butyl ester was removed with TFA in dichloromethane
to give optically pure (>99.5% ee) (R)-2-(3-oxo-1-tosyl-1,2,3,4-tet-
rahydropyrazin-2-yl)acetic acid
8 as stable and crystalline
material. The acid was then coupled with (R)-6-(piperidin-1-yl-
methyl)-1,2,3,4-tetrahydronaphthalen-1-amine13,14 to give 2a
directly. Alternatively the acid 8 was coupled to (R)-(5-amino-
5,6,7,8-tetrahydronaphthalen-2-yl)methanol9–11 to give alcohol
intermediate 9. The alcohol was oxidized with MnO2 to give the
aldehyde which was reductively aminated to give the final
compounds 2b–f. Acid 8 was coupled with other smaller amines
to give truncated amides 10, 11a–g, and 17–26. These smaller
amines are commercially available or from the Amgen building
block collection.
Specific syntheses were conducted for the chiral 4-amino-3,3-
dimethylpiperidine intermediates 31 and 34 (Scheme 2).16 First,
two methyl groups were installed at the
a-position of the
Boc-protected 4-piperidinone 27 under thermodynamic control.
The gem-dimethyl product 28 was then condensed with
⇑
Corresponding author. Tel.: +1 805 447 0078; fax: +1 805 480 1337.
E-mail address: wqian@amgen.com (W. Qian).
0960-894X/$ - see front matter Ó 2011 Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2011.11.112

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W. Qian et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1061–1067
O
O
O
O
O
S
N
S
O
H
S
N
H
N
H
N
N
N
O
O
O
O
N
H
O
N
H
O
N
H
O
N
N
N
2a
3
1a
Ki = 0.24 nM
Ki = 0.15 nM
Figure 1. Evolution of dehydro-oxopiperazine acetamides as B1 antagonists.
Ar
O2S
HN
Ar
O2S
HN
O
H2N
O
b
c
a
O
MeO
O
O
N
H
O
O
HO
O
HO
O
5
OMe
4
6
Ar
O
O
Ar
O
O
Ar
S
N
S
N
O2S
N
H
N
OH
O
d
e
O
O
O
N
H
O
N
H
O
N
H
O
8
7
9
i
f
g, h
OH
Ar
O
O
Ar
O
O
R3
N
S
N
S
N
H
N
R4
O
O
O
N
H
N
H
O
10, 11a-g, 17-26
2
NR1R2
Scheme 1. Reagents and conditions: (a) Ar-sulfonyl chloride, Na2CO3, THF/H2O; (b) 2,2-dimethoxyethanamine, EDCI, HOBT, THF; (c) p-TsOH, dioxane, 60 °C; (d) TFA, DCM; (e)
(R)-(5-amino-5,6,7,8-tetrahydronaphthalen-2-yl)methanol, EDCI, HOBT, DMF; (f) (R)-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-amine, EDCI, HOBT, DMF; (g)
MnO2, DCM. (h) HNR1R2, NaBH(OAc)3, DCE; (i) HNR3R4, EDCI, HOBT, DMF.
(S)-1-phenylethylamine in the presence of TiCl4 to form imine 29
with E-geometry. Diastereoselective reduction with NaBH4 at low
temperature afforded amine 30 with the S, S isomer as the major
product. Finally, hydrogenolysis afforded the chiral amine 31 in
>97% ee. Similarly, the R-isomer 34 can be obtained by using (R)-
1-phenylethylamine as the chiral auxiliary. These amines were
coupled to acid 8 and deprotected to give amides of interest
(11h, 12–14, and 11i). Further reductive amination provided alkyl-
ated analogs 11j–r, 15 and 16.
Because dehydro-oxopiperazine was a novel pharmacophore
that had not been studied extensively in the literature, we investi-
gated the chemical stability of 2a in a range of pH values at room
temperature by LCMS (Table 1). In general, no epimerization was
observed when 2a was exposed to acidic, neutral and basic condi-
tions, such as pH = 1.45, 1.97, 4.39, 7.0 and 10.04 for up to 4 days. A
small degree of parent compound degradation was observed at
pH = 1.45; no degradation was observed at pH = 2.0, 4.4 and 7.0;
some marked degradation was observed at pH = 10.04, resulted
in the detosylated product and toluenesulfinic acid. Therefore,
these results indicated that 2a is quite stable from acidic to neutral
conditions.
ingly, 2a is about 3.5-fold more potent than its saturated analog
1a14 (Ki = 45 pM vs 160 pM) in the binding assay. In the functional
assay 2a (IC50 = 0.115 nM) is about twice as potent as 1a
(IC50 = 0.22 nM). The activity of 2a was then determined in an
ex vivo isolated tissue bath assay using human umbilical vein
(HUV).17 In this test, the stress of tissue isolation up-regulates
the B1 receptor in umbilical vein segments. The B1 receptor selec-
tive agonist, des-Arg9-bradykinin, produces smooth muscle con-
tractions in a dose-dependent manner. In this assay, 2a has a Kb
value of 32 pM and is 10-fold more potent than compound 1a
(0.34 nM).14 These data indicate that the dehydro-oxopiperazine
provides further potency enhancement compared to the oxopiper-
azine scaffold.
We then examined the SAR of different basic amino groups on
compound 2a (Table 2). The primary amine 2b is 36-fold less po-
tent than the piperidine analog 2a in the binding assay. Interest-
ingly, compared to saturated oxopiperazine analog 1b it is about
37-fold more potent in the binding assay.14 The addition of small
alkyl groups (2c–2f) to the amino moiety slightly improved the
binding affinity. All these analogs have reasonable in vitro meta-
bolic stability (HLM < 100 lL/min/mg).
Compound 2a was assayed for its in vitro binding (Ki) and func-
tional (IC50) potency against human B1 receptor (Table 2). The
details of the assays have been described previously.9,11 Surpris-
The SAR between 2b and 1b suggests that the dehydro-
oxopiperazine pharmacore can provide more significant potency
enhancement over the oxopiperazine core when the right hand

W. Qian et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1061–1067
Ph Ph
1063
O
O
N
NH
NH2
d
a
b
c
e
N
Boc
N
Boc
N
Boc
N
Boc
30
N
Boc
31
27
28
29
Ph
Ph
NH
N
NH2
d
e
N
N
N
Boc
Boc
Boc
33
34
32
Ar
O
O
Ar
O
O
Ar
O
O
S
N
S
N
S
N
H
H
N
N
OH
f, g
i
NH
NH
N
R1
O
O
O
N
H
O
N
H
O
N
H
O
R2
8
11h, 12-14
11j-r, 15, 16
h, g
Ar
O
S
N
O
H
N
O
N
H
O
11i
Scheme 2. Reagents and conditions: (a) MeI, NaH, THF, 61%; (b) (S)-1-phenylethylamine, TiCl4, NEt3, DCM, 60 °C, 98%; (c) (R)-1-phenylethylamine, TiCl4, NEt3, DCM, 60 °C,
95%; (d) NaBH4, ethanol, À78 °C to À20 °C, 70% for 30 and 70% for 33; (e) H2, Pd/C, MeOH, 60% for 31 and 62% for 34; (f) 31, EDCI, HOBT, DMF; (g) HCl; (h) 34, EDCI, HOBT,
DMF, 80%; (i) R1COR2, NaBH(OAc)3, DCE.
Table 2
Table 1
SAR study of oxopiperazine and dehydro-oxopiperazine series
Chemical stability of compound 2a at room temperature
Buffer Apparent Epimerization Parent degradation Parent degradation
4 daya (%)
O
O
pH
pH
4 day
1 day (%)
O
O
S
N
S
N
H
N
H
N
1.45
1.65
0
0
0
0
0
0.01
0
0
0
3.92
0.20
0
0.06
0.03
12.88a
1.97
4.39
7.0
2.47
5.13
7.76
O
O
N
H
O
N
H
O
10.04 10.80
a
The detosylated product increased from 0% at time zero to 7.66% by day four.
X
1
2
X
Also, toluenesulfinic acid was not detected at time zero but increased to 4.76% by
day four.
HLMb
kg)
(lL/min/
a
Compound
X
Kia (nM)
IC50 (nM)
1a
1b
2a
2b
2c
2d
2e
2f
Piperidine
NH2
Piperidine
NH2
0.16 0.08
60 43
0.045 0.015 0.115 0.027 <50
1.64 0.014
1.25 0.009
0.22 0.07
238 253
<50
<50
side moieties are less potent in the latter series. It was therefore of
interest to investigate whether, in the presence of the dehydro-
oxopiperazine core, the relatively heavy right hand tetralin amine
moiety of 2 could be replaced by smaller groups in order to reduce
molecular weight without compromising potency.
Our initial attempt to reduce the molecular weight began with
simple removal of the benzylic amine to give the parent tetralin
core (Table 3). The potency of the truncated compound 10a was
maintained at low single digit nanomolar. It should be pointed
out that maintaining the tetralin was crucial, as cleaving (10b) or
shrinking (10c) the six-membered ring led to significant loss of
activity. Subsequently, the effect of small, non-basic amine groups
such as methoxy on the tetralin core was also explored. While ana-
log 10e with 6-methoxy group has similar potency compared to
0.28 0.003 <50
0.21 0.15 <50
NMe2
Pyrrollidine 0.197 0.026 0.084 0.014 <50
NHcPr
NHCH2tBu
0.56 0.35
0.48 0.066
0.23 0.14
0.40 0.28
<100
<100
a
Ki and IC50 are reported as the average SD of at least two or more
determinations.
The experiments are performed with two replicates for each compound. The
percent difference between replicates must be less than or equal to 20% in order for
the results to be considered valid.
b
the parent compound 10a, the other two regioisomers 10d and
10f are significantly less active.

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W. Qian et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1061–1067
Table 3
Table 3 (continued)
SAR study on truncated tetralin amide without basic amine
a
Compound
R
hB1 IC50 (nM)
HLMb
<50
(lL/min/mg)
O
S
N
O
H
N
10m
1.47 0.05
1.32 0.13
OH
O
R
O
N
H
O
Compound
R
hB1 IC50 (nM)
HLMb
514
(l
L/min/mg)
S
a
10n
<50
O
a
IC50s are reported as the average SD of at least two or more determinations.
The experiments are performed with two replicates for each compound. The
10a
3.3 1.1
b
percent difference between replicates must be less than or equal to 20% in order for
the results to be considered valid.
c
ND: not determined.
10b
10c
836 103
NDc
NDc
Table 4
SAR on small heterocyclic amides
94.7 10.7
O
S
N
O
H
N
R
O
10d
10e
10f
178 51.9
8.95 1.55
36.1 8.3
357
163
NDc
N
H
O
O
HLMb
147
(lL/min/mg)
a
Compound
R
hB1 IC50 (nM)
990 795
11a
11b
11c
314 109
NDc
212
O
25.9 15.3
O
O
11d
17.7 1.7
264
10g
10h
10i
18.7 1.4
21.6 1.9
72.2 47.4
96 31.5
40.8 6.0
<100
<50
450
<50
104
11e
11f
2040 665
83.9 5.3
<50
<50
O
NH
NH
11g
11h
11i
11j
11k
11l
25.2 2.5
0.43 0.26
1210 701
0.42 0.09
0.63 0.03
0.51 0.17
<100
<100
NDc
<14
O
N
O
NH
NH
N
O
10j
NH
10k
O
<50
N
10l
7.51 2.27
192
<50
O
N
O

W. Qian et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1061–1067
1065
Upon removal of the polar benzylic amines, the in vitro meta-
bolic stability dropped substantially as indicated by the high
HLM of 10a. Attaching methoxy groups led to little improvement.
To address this liability, an oxygen atom was inserted into the
bicyclic system. As a result, the HLM of 10g was improved to the
Table 4 (continued)
a
Compound
R
hB1 IC50 (nM)
HLMb
27
(lL/min/mg)
11m
0.86 0.61
1.38 0.22
1.09 0.31
N
N
N
N
desired range (<100 lL/min/mg) at the cost of 5-fold decrease in
potency. We then shifted our focus to other heteroatom insertion
on the aliphatic region in 10h. While replacement of oxygen by
an NH group maintained potency, acylation on NH group (10i)
was detrimental to both potency and metabolic stability. The lac-
tam analog 10j was metabolically stable but less active than 10a.
Our next step was to move the oxygen one atom out of the ring.
It turned out that ketone 10k was even less potent than 10g. Inter-
estingly, the ketal derivative 10l was 5-fold more potent than ke-
tone 10k. This suggests that oxygen attached to a sp3 carbon is
more favorable than the planar sp2 analog. In order to reduce the
microsomal clearance of the ketal while maintaining desirable
sp3 geometry, the ketone was reduced to give secondary alcohol
10m. This led to over 20-fold increase in potency and good meta-
bolic stability. Following the same sp3 hypothesis, the tetralin core
was replaced by a cyclic sulfone (10n) to give 1.3 nM functional po-
tency and acceptable liver microsomal clearance.
Given the promising results from the removal of the benzylic
amine, we then explored possibility to further reduce the size of
the molecules by truncating the benzo-fused group of the amine
moiety (Table 4). The cyclohexyl amide analog 11a exhibited
IC50 = 990 nM in the functional assay. 4-Methyl substitution on
the cyclohexyl (11b) increased the potency by 3-fold. More signif-
icant enhancement was observed with the 2-methyl analogue 11c
11n
11o
405
NDc
11p
11q
1.12 0.13
0.74 0.31
258
24
N
N
11r
0.247 0.02
<14
a
IC50s are reported as the average SD of at least two or more determinations.
The experiments are performed with two replicates for each compound. The
b
percent difference between replicates must be less than or equal to 20% in order for
the results to be considered valid.
c
ND: not determined.
Table 5
Further SAR
O
Ar
R1
N
S
N
O
R2
O
N
H
O
R1NR2
hB1 IC50 (nM)
HLMb
<100
(lL/min/mg)
a
Compound
Ar
H
N
11h
4-MePh
0.43 0.26
0.65 0.02
0.28 0.01
0.31 0.02
0.28 0.01
0.22 0.01
NH
NH
NH
NH
N
H
N
12
13
14
15
16
3,4-Cl2Ph
<50
<14
21
H
N
2,3-Cl2Ph
H
N
2,5-Me2-4-ClPh
2,5-Me2-4-ClPh
2,3-Cl2Ph
H
N
87
H
N
33
N
N
17
18
19
2,3-Cl2Ph
20.3 10.5
130 46
19 6.5
101
NDc
265
N
N
N
2,3-Cl2Ph
N
N
2,5-Me2-4-ClPh
(continued on next page)

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W. Qian et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1061–1067
Table 5 (continued)
a
Compound
Ar
R1NR2
hB1 IC50 (nM)
HLMb
NDc
(lL/min/mg)
N
20
21
2,5-Me2-4-ClPh
152 108
N
N
2,5-Me2-4-ClPh
2,5-Me2-4-ClPh
38 24
235
NDc
N
N
N
22
23.4 6.3
23
24
2,5-Me2-4-ClPh
2,5-Me2-4-ClPh
2.7 0.22
64
60
N
N
N
N
4.75 3.22
H
N
25
2,5-Me2-4-ClPh
2,5-Me2-4-ClPh
136 105
1.53 1.0
NDc
28
N
N
H
N
26
a
IC50s are reported as the average SD of at least two or more determinations.
The experiments are performed with two replicates for each compound. The percent difference between replicates must be less than or equal to 20% in order for the
b
results to be considered valid.
c
ND: not determined.
even as a mixture of stereoisomers. The gem-2,2-dimethyl com-
pound 11d removed one stereocenter and further improved the
potency to 17 nM. Not surprisingly, this more lipophilic derivative
suffered higher metabolic clearance and the metabolite ID indi-
cated that the gem-2,2-dimethyl cyclohexyl unit was the major
site for metabolism. To address this issue, an oxygen atom was in-
serted into the six-membered ring, resulting in much better micro-
somal clearance and comparable potency (11g). Insertion of a basic
nitrogen atom (11f) led to over 100-fold enhancement in potency
and better stability compared to 11a. The functional potency was
significantly improved to sub-nanomolar in 11h by combining
the gem-2,2-dimethyl of 11d and the basic nitrogen of 11f. Analog
11i, the stereoisomer of 11h, was over 2000-fold less potent. N-
alkylation on 11h had minimum effect on antagonist activity
(11j–r).
In summary, sulfonyl dehydro-oxopiperazine acetamides are a
novel class of compact and stable B1 receptor antagonists. Com-
pared to its saturated counterpart, this highly potent pharmaco-
phore enables reduction of the size of the right hand side tetralin
amine moieties while maintaining the potency at low nanomolar
in B1 functional assay. This work also suggests that the dehydro-
oxopiperazine scaffold might have broader application in medici-
nal chemistry in the future.
Acknowledgment
The authors thank Dr. Jennifer Allen for insightful discussions.
References and notes
Having confirmed that high potency can be maintained with
much smaller heterocycles on the right hand side, we then looked
into the effect of different aryl sulfonyl groups (Table 5). No signif-
icant improvement was obtained with more lipophilic substitu-
tions (12–16). No dramatic decrease in metabolic stability was
observed in these compounds possessing a basic amine moiety of
lower molecular weight compared to 2a.
In order to further explore the SAR, the aryl sulfonyl dehydro-
oxopiperazine pharmacophore was coupled to a series of small sec-
ondary amines on the right hand side (17–26, Table 5). Interest-
ingly, the distance and the relative geometry between the two
nitrogen atoms had a dramatic effect on potency. While pyrrolidine
and piperidine analogs afforded moderate potency, the seven- and
eight-membered ring analogs such as 23 and 24 can drive the
functional IC50 to low single digit nanomolar. Two more rigid
bicyclic diamines were also investigated. The spiral pyrrolidine
compound 26 was much more potent than the fused pyrrolidine
analogue 25.
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