Indazole derivatives as novel bradykinin B1 receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2010.09.121

A new class of indazole-derived bradykinin B₁ antagonists and their structure-activity relationships (SAR) is reported. A number of compounds were found to have low-nanomolar affinity for the human B₁ receptor and possess acceptable P-gp and pharmacokinetics properties.

Full text of DOI:10.1016/j.bmcl.2010.09.121

Bioorganic & Medicinal Chemistry Letters 20 (2010) 7011–7014
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Indazole derivatives as novel bradykinin B1 receptor antagonists
Vera Bodmer-Narkevitch a, , , Neville J. Anthony a, Victoria Cofre a, Samson M. Jolly a, Kathy L. Murphy b,
⇑
Richard W. Ransom b, Duane R. Reiss b, Cuyue Tang c, Thomayant Prueksaritanont c, Douglas J. Pettibone b,
Mark G. Bock a, Scott D. Kuduk a
a Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA
b Neuroscience Drug Discovery, Merck Research Laboratories, West Point, PA 19486, USA
c Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A new class of indazole-derived bradykinin B1 antagonists and their structure–activity relationships
(SAR) is reported. A number of compounds were found to have low-nanomolar affinity for the human
B1 receptor and possess acceptable P-gp and pharmacokinetics properties.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 20 August 2010
Revised 22 September 2010
Accepted 23 September 2010
Available online 29 September 2010
Keywords:
Bradykinin
Antagonist
Indazole
P-Glycoprotein
The kinin peptides exhibit a wide range of biological activities
including pain, inflammation, vasodilatation, and smooth muscle
contraction. Their biological response is mediated by the bradyki-
nin B1 and B2 receptors.1 While the B2 receptor is widely expressed
in many cell types, the B1 receptor was shown to be generally ab-
sent from normal tissues. However, it can be rapidly induced fol-
lowing injury.2 Data from transgenic bradykinin B1 receptor
knockout mice has implied a role for the receptor in pain,3 and
the need for novel pain modulators exempt of tolerance or abuse
issues related with opiates has since prompted the development
of selective bradykinin B1 receptor antagonists.
While peptide antagonists for the B1 receptor were discovered
over 2 decades ago,4 a number of non-peptidic antagonists have
been disclosed to date.5–8 In parallel to investigating the previously
reported biphenyl motif,6c–8 a 1-phenyl-1H-indazole (1, Fig. 1) was
identified. Accordingly, an SAR examination of the structural
requirements of both the indazole moiety and the cyclopropylcarb-
oxamide part were performed en route for an optimal bradykinin
B1 antagonist, and are described herein.
alytic system in the presence of potassium phosphate9 provided
amines 4a–d after subsequent hydrolysis of the acetamide groups
in acidic conditions. EDC–promoted coupling of 4a–d with cyclo-
propanecarboxylic acid derivative 5 delivered amines 6a–d after
cleavage of the tert-butyl carbamate in acidic conditions. The bio-
logical study targets 7a–v were prepared employing standard
amide bond forming procedures.
Acetamide 8, obtained after N-arylation of 3-bromo-1H-inda-
zole 3c with 2, was subjected to Suzuki coupling conditions10 with
the appropriate boronic acids to deliver acetamides 9a–d (Scheme
2), which subsequently underwent acidic hydrolyses and EDC-cou-
pling reactions with 10 to provide targets 7w–z. Compound 11 was
F
F
H
H
F
F
F
F
N
N
O
O
O
NH
O
NH
The featured compounds were prepared according to Scheme 1.
Copper-catalyzed N-arylation of commercially available indazoles
3a–d and bromide 28 using the trans-diaminocyclohexane/CuI cat-
CO2Me
F
F
F
N
N
⇑
Corresponding author. Tel.: +1 267 218 2045; fax: +1 610 917 7391.
E-mail addresses: vbodmer@mac.com, vera.q.bodmer@gsk.com (V. Bodmer-
Narkevitch).
Cl
1, hBK1 K1 = 11 nM
hBK1 K1 = 1.5 nM
Pgp ratio = 4.1
Present address: GlaxoSmithKline, 1250 South Collegeville Road, UP12-205,
Collegeville, PA 19426, USA.
Figure 1. Lead indazole bradykinin B1 antagonist 1.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.09.121

7012
V. Bodmer-Narkevitch et al. / Bioorg. Med. Chem. Lett. 20 (2010) 7011–7014
Table 1
NH2
O
Structural modifications of the indazole ring to improve
bradykinin B1 receptor affinities
H
N
NH
F
a)
b)
+
N
F
N
N
O
N
H
N
Br
R
OMe
4a X=C, R=H
4b X=C, R=Cl
4c X=C, R=Br
4d X=C, R=OH
3a R=H
2
O
3b R=Cl
3c R=Br
3d R=OH
R
O
NH
F
NHBoc
OH
N
N
O
H
N
R'
NH2
5, c), d)
R
O
O
O
7a-z, 11, 12
NH
F
NH
e)
Compda
R
hBK1 Ki (nM)b
7a
7w
7x
7y
7z
7b
7u
7v
11
12
H
Me
Et
11
1.3
19
33
82
0.67
0.81
335
21
F
N
N
N
N
c-C3H5
Ph
R
R
Cl
Br
7a X=C, R=H
7b-t X=C, R=Cl
7u X=C, R=Br
7v X=C, R=OH
6a X=C, R=H
6b X=C, R=Cl
6c X=C, R=Br
6d X=C, R=OH
OH
OMe
CN
2.4
Scheme 1. Reagents and conditions: (a) CuI, trans-1,2-diaminocyclohexane, K3PO4,
dioxane; (b) anhyd HCl, MeOH, 70 °C; (c) 5, 1-[3-(dimethylamino)-propyl]-3-
ethylcarbodiimide hydrochloride (EDC), 1-hydroxybenzotriazole (HOBt), Et3N,
CH2Cl2; (d) anhyd HCl, EtOAc, 0 °C; (e) R0CO2H, EDC, HOBt, Et3N, CH2Cl2.
a
All compounds are >95% pure by LC/MS at 215 nm
and characterized by 1H NMR and HRMS.
b
Values represent the numerical average of at least
two experiments. Interassay variability was 25% for
the binding assays.
NHR''
NHR''
Ki values (nM) were determined radiometrically using the
appropriate radioligand and Chinese hamster ovary (CHO) cells
stably expressing the human B1 and the human B2 receptors.
The un-substituted indazole (7a, Table 1) provided a hBK1 Ki va-
lue of 11 nM. Optimization initially involved systematic substitu-
tion of each indazole hydrogen (data not shown); however, it
was rapidly concluded that the most promising compounds de-
rived from substitution at the 3-position (Table 1). All compounds
aA or aB
F
N
F
N
N
N
Br
R
9a R''=Ac, R=Me
9b R''=Ac, R=Et
9c R''=Ac, R=c-C3H5
9d R"=Ac, R=Ph
4c R''=H
8 R''=Ac
were B1 selective (Ki >10 lM vs the B2 receptor).
Among the alkyl and cycloalkyl derivatives examined (7w–z),
the 3-methyl indazole 7w was moderately potent (hBK1 Ki = 1.3).
A substantial drop in binding affinity was observed with oxophilic
substituents (compounds 7v and 11). The cyano-derivative 12
exhibited a 4.5-fold increase in affinity relative to 7a; however,
sub-nanomolar activity was achieved only with a 3-halogen substi-
tuent (7b and 7u).
An additional phenyl group decreases the compound’s binding
ꢀ7 fold (compound 7z versus 7a). Removal of the fused aryl ring
of the indazole system leading to a pyrazole (13a, Fig. 2) induced
N
O
OMe
H
N
b), c)
O
N
O
OH
10
O
OMe
H
N
O
O
NH
F
O
N
O
N
H
N
H
N
OMe
OMe
N
O
O
7w R=Me
7x R=Et
7y R=c-C3H5
7z R=Ph
O
O
NH
F
N
NH
F
R
N
N
Scheme 2. Reagents and conditions: (a) method A: RB(OH)2 Pd(PPh3)2Cl2, Cs2CO3,
7:3:1 dioxane/EtOH/H2O, 80 °C; method B: RB(OH)2 Pd(dba)2, Ph5FcP(t-Bu)2, K3PO4,
toluene, 80 °C; (b) anhyd HCl, MeOH, 70 °C, quant; (c) 10, 1-[3-(dimethylamino)-
propyl]-3-ethylcarbodiimide hydrochloride (EDC), 1-hydroxybenzotriazole (HOBt),
Et3N, CH2Cl2.
N
N
R'
R
R
13a, R=H, R1=H, hBK1 Ki = 220 nM 14a, R=H, hBK1 Ki = 27 nM
13b, R=Ph, R1=H, hBK1 Ki = 610 nM 14b, R=Me, hBK1 Ki = 10 nM
13c, R=H, R1=Ph, hBK1 Ki = 510 nM
prepared starting from 3-methoxy-1H-indazole.11 The cyano-
derivative 12 was obtained after palladium-catalyzed cyanation
of bromide 8,12 in a similar fashion.
Figure 2. Pyrazole and 4,5,6,7-tetrahydroindazole containing analogs.

V. Bodmer-Narkevitch et al. / Bioorg. Med. Chem. Lett. 20 (2010) 7011–7014
7013
Table 2
a 20-fold decrease in binding affinity to the human B1 receptor. The
3 or 4-phenyl substituted pyrazoles 13b and 13c were found to be
similarly less active. Furthermore, the 4,5,6,7-tetrahydroindazole
derivatives 14a and 14b showed hBK1 Ki of 27 and 10 nM, respec-
tively, indicating that the fused aromatic heterocyclic indazole sys-
tem is required to achieve sub-nanomolar binding values.
Having identified the 3-chloro-indazole as a potent modifica-
tion, our attention turned to examining the role that the differently
substituted cyclopropylamino acid amides have within this series.
Data for selected compounds is shown in Table 2.
Effect of the variation of the cyclopropylamino acid amide on the binding affinity and
on the P-gp efflux of novel indazole BK1 antagonists
H
N
R'
O
O
NH
The methoxyisoxazole derivative 10b proved fairly potent with
a Ki of 0.67 nM. In the 1,3-thiazole series (compounds 10c–e) the 2-
methoxy derivative 10d was the most active with a Ki of 0.29 nM.
The un-substituted thiazole derivative 10c showed comparable po-
tency, however, introducing a methyl function in the 4-position
lowered the binding affinity to 8.2 nM (10e). Incorporation of an
additional heteroatom at the 2-position of the thiazole (10f) brings
the affinity back to a sub-nanomolar value; however, the 4-
methyl-1,2,3-thiadiazole ring proved extremely vulnerable
in vitro in human liver microsomes (data not shown). The 3-pyrrol-
o amide 10g is a potent compound (Ki = 0.38 nM) with increased
stability in human liver microsomes.
Pyridyl cyclopropylcarboxamides (for example 10h) proved
most potent at the 3-position. Substituting the 2- or 4-positions
led to significant decrease in affinity (data not shown), while the
5- and 6-positions proved tolerant to substitution. For example,
the 6-methylnicotinamide (compound 10i) gave comparable
binding to 10h (hBK1 Ki = 1.4 nM), while the 6-bromonicotinamide
carried a threefold increase in affinity (10j). Substitution at the
5-position provided several subnanomolar activity compounds
(10k–p), with 5-bromopyridine 10p of note (hBK1 Ki of 0.12 nM).
A key issue with these compounds was susceptibility as sub-
strates for the efflux transporter, P-glycoprotein (P-gp). We have
previously observed that pyridine derivatives in the biphenyl ser-
ies6g proved to be good substrates for human P-gp, so select inda-
zole compounds were consequently evaluated in a P-gp transport
assay13 (Table 2).
Compounds with P-gp directional transport ratios less than 2.5
are generally not considered substrates. Optimal passive cell per-
meability (Papp) should usually exceed 15. Analogs 10b–f showed
good permeability and were not substrates for human P-gp. How-
ever, the otherwise promising pyrazole derivative 10g showed a
significant P-gp transport ratio of 55.6.
Pyridine derivatives 10k, 10o, and 10p were not substrates for
human P-gp, and possessed sufficient (>15) cell permeability.
Overall, the P-gp profile of indazole containing compounds can
possess adequate P-gp profiles with the appropriate amide
modification.
In the diazine series, going from pyridazine 10q to pyrimidine
10r and pyrazine 10s reduced the undesired P-gp efflux but the de-
sired binding affinity decreased as well. Of note, chloropyrazine
analog 10t was reasonably potent with a low P-gp ratio of 1.3.
As far as the stability of the 3-halo-indazoles is concerned,
while we have not looked for displacement with biological nucle-
ophiles, based upon our experience with these systems, direct dis-
placement would not be expected.
Indazoles with acceptable binding and P-gp profiles were eval-
uated for their rat and dog pharmacokinetic properties (Table 3).8
In the thiazole series, the 2-methoxy-1,3-thiazole 10d displayed
high clearance and a low bioavailability in rat. The 5-methoxynic-
otinamide analog 10m showed a significant drop in rat half-life
and a poor bioavailability. These parameters could be notably im-
proved with the 5-bromonicotinamide derivative 10p: in rat,
which displayed fair oral bioavailability, a half-life of 3 h and a
low clearance of 2.5 mL/min/kg. In dog the compound retained
low clearance with a half-life as high as 7.6 h. Another promising
F
N
N
Cl
10b-t
Compda
R
hBK1 Ki (nM)b
P-gpc
1.6
Papp
N
O
10b
0.67
26
OMe
OMe
N
10c
0.54
2.8
19
S
N
10d
10e
10f
0.29
8.2
1.8
—
14
—
S
N
S
N
0.71
0.38
1.5
2.3
55.6
—
21
19
—
N
S
NH
N
10g
10h
N
N
N
N
N
10i
10j
10k
1.4
—
—
Br
0.49
0.47
2.2
1.9
8.2
22
10l
0.30
0.52
0.37
0.20
0.12
89.0
5.3
7.5
2.5
2.3
18
21
24
15
13
OH
OMe
F
N
N
N
N
10m
10n
10o
10p
Cl
Br
N
N
N
N
10q
10r
0.65
0.18
29.4
5.9
25
24
(continued on next page)

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V. Bodmer-Narkevitch et al. / Bioorg. Med. Chem. Lett. 20 (2010) 7011–7014
Table 2 (continued)
References and notes
Compda
R
hBK1 Ki (nM)b
P-gpc
1.6
Papp
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Marceau, F.; Regoli, D. Nat. Rev. 2004, 3, 845.
N
10s
16.5
30
N
N
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10t
1.2
1.8
24
N
Cl
All compounds are >95% pure by LC/MS at 215 nm and characterized by 1H NMR
and HRMS.
Values represent the numerical average of at least two experiments. Interassay
variability was 25% for the binding assays.
a
b
c
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Cumberbatch, M. J.; Hill, R. G.; Rupniak, N. M. J. Can. J. Physiol. Pharmacol. 2002,
80, 264.
Values represent the numerical average of three experiments.
Table 3
Pharmacokinetic properties of selected indazole derivatives
Compd
Rat PKa
t1/2
Dog PKb
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Lynch, J. J.; O’Malley, S. S.; Miller, P. J.; Chen, T.-B.; Harrell, C. M.; Chang, R. S. L.;
Sandhu, P.; Ellis, J. D.; Bondiskey, P. J.; Pettibone, D. J.; Freidinger, R. M.; Bock,
M. B. J. Med. Chem. 2003, 46, 1803; (b) Su, D.-S.; Markowitz, M. K.; DiPardo, R.
M.; Murphy, K. L.; Harrell, C. M.; O’Malley, S. S.; Ransom, R. W.; Chang, R. S. L.;
Ha, S.; Hess, J. F.; Pettibone, D. J.; Mason, G. S.; Boyce, S.; Freidinger, R. M.; Bock,
M. G. J. Am. Chem. Soc. 2003, 125, 7516; (c) Kuduk, S. D.; Ng, C.; Feng, D.-M.;
Wai, J. M.-C.; Chang, R. S. L.; Harrell, C. M.; Murphy, K. L.; Ransom, R. W.; Reiss,
D.; Ivarson, M.; Mason, G.; Boyce, S.; Tang, C.; Prueksaritanont, T.; Freidinger, R.
M.; Pettibone, D. J.; Bock, M. G. J. Med. Chem. 2004, 47, 6439; (d) Feng, D.-M.;
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S. L.; Harrell, C. M.; MacNeil, T.; Tang, C.; Prueksaritanont, T.; Freidinger, R. M.;
Pettibone, D. J.; Bock, M. G. Bioorg. Med. Chem. Lett. 2005, 15, 2385; (e) Kuduk, S.
D.; Chang, R. K.; Ng, C.; Murphy, K. L.; Ransom, R. W.; Tang, C.; Prueksaritanont,
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Prueksaritanont, T.; Wallace, A. A.; Mei, Q.; Yu, J.; Bohn, D. L.; Clayton, F. C.;
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D.; Holahan, M. A.; Cook, J.; Hess, J. F.; Sain, N.; Urban, M. O.; Tang, C.;
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Org. Chem. 2002, 67, 5553.
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F%
CL
t1/2
CL
1.3
10b
10c
10d
10f
49
—
13
—
—
—
6
—
24
—
3.1
5.3
20.8
4.3
8.3
2.4
7.1
2.6
2.3
6.0
7.6
15.1
1.1
1.7
9.6
2.6
4.3
5.5
3.1
3.8
10.5
8.3
12.7
7.8
10j
10k
10m
10o
10p
10t
0.7
3.1
1.6
2.5
105
a
F% oral bioavailability, half-life is represented in hours, CL in mL/min/kg.
Sprague-Dawley rats (n = 3). Oral dose = 10 mg/kg, iv dose = 2 mg/kg in DMSO.
Interanimal variability was less than 20%.
b
Mongrel dogs (n = 2). Oral dose = 3 mg/kg, iv dose = 1 mg/kg in DMSO. Inter-
animal variability was less than 20% for all values.
pharmacokinetic profile in both rat and dog was observed for the
isoxazole derivative 10b.
In conclusion, SAR evaluation of a novel class of human BK1
receptor antagonists bearing a heteroaromatic ring system was
undertaken. The indazole portion of the molecule was identified
as a sensitive feature for the optimal binding to the receptor with
a chlorine at the 3-position of the indazole optimal for high recep-
tor affinity. SAR effects on P-gp efflux potential was examined for
these indazoles on the cyclopropylcarboxamide region identifying
5-bromonicotinamide 10p as a potent bradykinin B1 antagonist
possessing good pharmacokinetics properties. The result of this
study yielded a combination of structural features allowing for
the preparation of further compounds with novel properties as im-
proved bradykinin B1 antagonists.
Acknowledgments
12. Yang, C.; Williams, J. M. Org. Lett. 2004, 6, 2837.
13. Yamazaki, M.; Neway, W. E.; Ohe, T.; Chen, I.; Rowe, J. F.; Hochman, J. H.; Chiba,
M.; Lin, J. H. J. Pharmacol. Exp. Ther. 2001, 296, 723.
We would like to acknowledge Sandor L. Varga and Joan S. Mur-
phy for analytical support.