Aryl sulfonamides containing tetralin allylic amines as potent and selective bradykinin B1 receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2010.06.010

The bradykinin B1 receptor has been shown to mediate pain response and is rapidly induced upon injury. Blocking this receptor may provide a promising treatment for inflammation and pain. We previously reported tetralin benzyl amines as potent B1 antagonists. Here we describe the synthesis and SAR of B1 receptor antagonists with homobenzylic amines. The SAR of different linkers led to the discovery of tetralin allylic amines as potent and selective B1 receptor antagonists (hB1 IC₅₀ = 1.3 nM for compound 16). Some of these compounds showed modest oral bioavailability in rats.

Full text of DOI:10.1016/j.bmcl.2010.06.010

Bioorganic & Medicinal Chemistry Letters 20 (2010) 4593–4597
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Aryl sulfonamides containing tetralin allylic amines as potent and selective
bradykinin B1 receptor antagonists
a
a
a
a
a
Qingyian Liu a, , Wenyuan Qian , Aiwen Li , Kaustav Biswas , Jian Jeffrey Chen , Christopher Fotsch ,
Nianhe Han a, Chester Yuan a, Leyla Arik c, Gloria Biddlecome a, Eileen Johnson c, Gondi Kumar b,
Dianna Lester-Zeiner a, Gordon Y. Ng d, Randall W. Hungate a, Benny C. Askew a
*
a Chemistry Research and Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States
b Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States
c Department of Neuroscience, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States
d Department of Inflammation, 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:
The bradykinin B1 receptor has been shown to mediate pain response and is rapidly induced upon injury.
Blocking this receptor may provide a promising treatment for inflammation and pain. We previously
reported tetralin benzyl amines as potent B1 antagonists. Here we describe the synthesis and SAR of
B1 receptor antagonists with homobenzylic amines. The SAR of different linkers led to the discovery of
tetralin allylic amines as potent and selective B1 receptor antagonists (hB1 IC50 = 1.3 nM for compound
16). Some of these compounds showed modest oral bioavailability in rats.
Received 19 April 2010
Revised 28 May 2010
Accepted 2 June 2010
Available online 8 June 2010
Keywords:
Ó 2010 Elsevier Ltd. All rights reserved.
Homobenzylic amines
Allylic amines
Bradykinin B1
Receptor antagonist
Pain
Bradykinin B1 and B2 receptors are two distinctive G-protein
coupled receptors that mediate pathophysiological pathways in
pain and inflammation via similar signaling cascades.1–5 The B1
and B2 receptors are different not only in the structures of their nat-
ural agonists, but also in their biological expressions and patterns of
regulation. The B2 receptor is constitutively expressed in the central
and peripheral nervous system, vascular and tissue endothelium,
and on a number of inflammatory cells. The B1 receptor generally
exists at very low levels in normal states, and it is rapidly induced
following tissue injury.3–5 The B2 receptor is quickly desensitized
and internalized when activated by its ligands (bradykinin or kalli-
din). Preclinical studies suggest that the B2 receptor plays a role in
H
H
H
N
H
N
H
N
H
N
N
N
F3C
S
O
O
F3C
S
O
F3C
S
O
O
O
O
O
O
F
R1
X
N
N
R2
R3
X = H, F
1
2
Figure 1. Progression of SAR.
* Corresponding author. Tel.: +1 805 447 1713; fax: +1 805 480 3016.
E-mail address: qingyian@amgen.com (Q. Liu).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.06.010

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Q. Liu et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4593–4597
H2N
BocHN
H2N
H
N
OH
a, b
c, d
e
F3C
S
+
O O
O
S
I
OH
S
S
F
3
4
5
6b
H
N
H
N
H
N
H
H
N
H
N
N
F3C
S
F3C
F3C
S
O O
g
f
O
O O
O
O O
O
F
F
S
F
N
S
O
7
8
2
Scheme 1. Reagents and conditions: (a) Boc2O, DMF, rt, 12 h, 100%; (b) I2, PPh3, imidazole, ether/DCM, rt, 2 h, 91%; (c) 1,3-dithiane, BuLi, THF, À30 to 0 °C, 3 h, 60%; (d) HCl,
MeOH, rt, 12 h, 100%; (e) EDCI, HOBT, DMF, rt, 12 h, 90%; (f) Hg(ClO4)2, CaCO3, THF/H2O, rt, 1 h, 45%; (g) NaBH(OAc)3, piperidine, DCE, rt, 12 h, 55%.
acute wpain processing. In contrast, the B1 receptor is believed to
play a more active role in persistent pain and inflammation because
this receptor is not desensitized after activation by its natural ligands
(des-Arg(9)-BK or des-Arg(10)-kallidin).1 In animal models, B1
receptor agonists cause hyperalgesia, an effect that can be reversed
byperipherallyrestrictedpeptideB1receptorantagonists. Thisresult
can be further supported by the fact that B1 receptor knockout mice
have shown reduced sensitivity towards painful stimuli.6,7 These
experiments have demonstrated the therapeutic potential for novel
B1 antagonists as new treatments for inflammation and pain.
N3
OH
NH2
O
c
b
a
+
TfO
TfO
OH
TfO
TfO
12
11
9
10
H
N
H
N
H
N
F3C
S
O
d
F3C
S
O
O
e
O
O
O
OH
X
X
OTf
13
6a, X = H
6b, X = F
H
N
H
N
H
N
H
N
H
H
N
F3C
S
O
F3C
S
O
h
N
O
O
F3C
S
O
O
O
f, g
O
R3
X = H
=
O
N
X
X
R3
N
17
14
OH
15, X = H, R3 = varied amines
16, X = F, R3 = pyrrolidinyl
i
X = H
H
N
H
N
H
N
H
N
F3C
S
O
F3C
S
O
O
O
O
j, k
O
19
18
OH
N
Scheme 2. Reagents and conditions: (a) (R)-CBS, BMS, 93%; (b) DPPA, DBU, 85%; (c) PPh3, THF/H2O, 70%; (d) EDC, HOBt, 97%; (e) DPPF, Pd(OAc)2, Et3N, DMF, 62%; (f) MsCl,
NEt3, DCM; (g) Amines, DCM, 50–70% (over two steps); (h) H2, 5%Pd/Al2O3, 44%; (i) Et2Zn, ClCH2I, DCE, 70%; (j) Dess–Martin oxidation, 68%; (k) piperidine, NaBH(OAc)3, DCE,
48%.

Q. Liu et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4593–4597
4595
Several classes of non-peptidic B1 antagonists have been re-
ported.8–14 A pharmacophore found in one of the major classes of
B1 antagonists contains a lipophilic sulfonamide, a linker group,
and a basic amine. We have previously identified aryl sulfonyl
substituted b-phenylalanine tetralin and chroman system as novel
B1 antagonists by adding conformational constraints.15–17 It was
demonstrated that an aryl sulfonamide and a benzylic amine group
were essential for potency (e.g., compound 1). To better under-
stand the spatial requirement of the basic amine, the methylene
linker was extended by one more carbon, which resulted in com-
pound 2, our lead of the homobenzylic amine series.
One strategy that has been used by medicinal chemists to in-
crease potency is to decrease the flexibility of a compound. To
fine-tune the conformation of the tetralin system, we began by
introducing different substituents at the benzylic position of the
tetralin using the parent b-phenylalanine trifluoromethylphenyl-
sulfonamide 2 (Fig. 1). After the favored substituents at the benzylic
position were identified, the SAR of different amine moieties was
explored.
The compounds of interest were prepared by two different syn-
thetic routes as shown in Schemes 1 and 2. The synthesis of elon-
gated 1,6-disubstituted tetralin derivatives 2 started from tetralin
aminoalcohol 317 (Scheme 1). Selective Boc-protection of the ami-
no group followed by iodination of the benzylic alcohol afforded 4.
Iodide displacement with the lithium salt of 1,3-dithiane and
cleavage of the Boc group provided amine 5. Coupling of 5 with
acid 6b16 gave amide 7. Treatment of 7 with Hg(ClO4)2 provided
the aldehyde functionality in 8. Reductive amination of 8 with
piperidine provided homobenzylic amine 2.
rating a double bond (compound 15a) further boosted the potency
to 41 nM.
Encouraged by the result from the tetralin allyl piperidine 15a,
we explored in detail the effect of different amine substitutions on
the allyl linker (Table 2). Pyrrolidine compound 15b with an
IC50 = 10 nM, was threefold more potent than piperidine analog
15a (previous SAR in the benzylamine series showed that piperi-
dine provided the most potent compound20). Tertiary amine ana-
logs with small substituents (15e and 15f) were much less
potent than pyrrolidine analogs (15b–15d). Interestingly, the ste-
reochemistry of the 3-hydroxy group on the pyrrolidine ring had
an impact on the potency as demonstrated by the 3–4-fold IC50 dif-
ference between 15c and 15d. For analogs with secondary amines
(15g–15m), 2-methoxyethanamine 15h was the most potent with
IC50 = 23 nM. Cyclopropylmethylamine was the least potent amine
(compound 15i, IC50 = 105 nM). In the chroman benzyl amine ser-
ies16, the replacement of b-phenylalanine with 4-F-b-phenylala-
nine resulted in a significant increase in potency. Thus a similar
analog 16 was prepared and indeed it was sevenfold more potent
than the parent compound 15b. Compared to the original lead 2,
a 40-fold improvement in functional potency was achieved with
compound 16 (IC50 = 1.3 nM). In addition, all compounds were
selective for the B1 receptor with IC50s >20 lM against B2.
Finally, we examined the pharmacokinetics of selected com-
pounds in rats (Table 3). Similar rat PK properties were observed
for compounds with allylic amines (compounds 15b and 15k)
and the benzylic amine (compound 1). These compounds showed
moderate in vivo and in vitro clearance and gave 10–15% oral
bioavailability.
The synthesis of allylic amine derivatives 15 and 16 is outlined
in Scheme 2. Corey–Bakshi–Shibata reduction of tetralone 917 led
to S-alcohol 10 in >99% ee. Compound 10 was then subjected to
treatment with DPPA and DBU to provide R-azide 11. Selective
reduction using PPh3 gave the corresponding tetralin amine 12.
This amine was then coupled with acid 6a or 6b to give amide
13 with a triflate group at the 6-position of the tetralin core. Palla-
dium mediated cross-coupling with allylic alcohol gave compound
14.18,19 Final installation of the amino diversity at the allylic posi-
tion in 15 and 16 was achieved in two steps: the allylic alcohol in
14 was converted to the mesylate, which was displaced with
amines. Reduction of the double bond with 5% palladium on alu-
mina gave compound 17 as a mixture of two diastereomers. The
cyclopropylmethyl amine 19 was prepared from 14 through cyclo-
propylation of the double bond, oxidation of the alcohol and reduc-
tive amination with piperidine.
In summary, we have described our efforts toward expanding
structural diversity of B1 antagonists with tetralin homobenzyl
amines having different a-substitutions. The SAR of different link-
ers led to the discovery of allylic amines as potent B1 antagonists.
The most potent compound in this series, compound 16, showed a
potency of 1.3 nM in the B1 functional assay, which represented a
40-fold improvement compared to the initial lead, compound 2.
Compounds 15b and 15k showed moderate rat in vivo clearance.
Table 1
SAR of different linkers
H
N
H
N
F3C
S
O O
O
The compounds synthesized in Schemes 1 and 2 were tested in
the human B1 receptor binding assay and human B1 agonist-in-
duced cellular calcium flux functional assay. Both assays have been
discussed previously.15 Results are reported as the average of at
least two independent experiments. The variance in the measure-
ments is expressed as the standard error of the mean (SEM). The
SAR studies disclosed below were based on the IC50 data from
the cellular calcium flux functional assay. Similar trends were ob-
served for the Ki values in the binding assay.
R
Compd
R
Binding Ki SEM (nM)
Functional IC50 SEM (nM)
N
17
34 10
316 54
Compound 2 was an early example from our efforts of a homo-
benzylic amine that showed moderate potency (hB1 binding
Ki = 15 nM, hB1 functional IC50 = 66 nM). Encouraged by this initial
result, we focused on improving the potency of this series. We first
investigated the effect of different linkers on the potency. All the
compounds were derived from 6a, which had an unsubstituted
central aromatic ring. We intended to modulate the conformation
of the tetralin substituents (R) by varying the size of the benzylic
substitutions (see Table 1). Compound 17, which is similar to com-
R, S
19
14
1
88 75
N
N
15a
3.3 0.1
41 12
pound 2 except the a-methyl and 4-F groups, had an IC50 = 316 nM.
Replacing the benzylic methyl with a cyclopropyl group resulted in
compound 19, which was threefold more potent than 17. Incorpo-

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Q. Liu et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4593–4597
Table 2
SAR of allylic amines
H
N
H
N
F3C
S
O
O
O
X
R3
Compd
15a
X
H
H
R3
Binding Ki SEM (nM)
3.3 0.1
Functional IC50 SEM (nM)
41 12
N
N
15b
0.7 0.1
9.7 2.9
OH
15c
15d
H
H
3.5 0.9
12 0.3
3.9 1.3
15 0.1
N
OH
N
N
N
15e
15f
H
H
12
2
206 36
154 39
78 12
OH
O
15g
15h
15i
H
H
H
21
42
16
6
4
2
32 18
NH
NH
23
7
N
H
105 54
15j
H
11
5
78
4
N
H
15k
15l
H
H
4.6 0.5
3.4 0.6
42 18
44 22
N
H
N
H
15m
16
H
F
30 15
ND
47
2
N
H
1.3 0.0
N
Table 3
7. Ferreira, J.; Campos, M. M.; Araujo, R.; Bader, M.; Bader, M.; Pesquero, J. B.;
Calixto, J. B. Neuropharmacology 2002, 43, 1188.
Rat pharmacokinetics of selected compounds
8. Gougat, J.; Ferrari, B.; Sarran, L.; Planchenault, C.; Poncelet, M.; Maruani, J.;
Alonso, R.; Cudennec, A.; Croci, T.; Guagnini, F.; Urban-Szabo, K.; Martinolle, J.-
P.; Soubrie, P.; Finance, O.; Le Fur, G. J. Pharmacol. Exp. Ther. 2004, 309, 661.
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J. J.; Wai, J. M. C.; DiPardo, R. M.; Murphy, K. L.; Ransom, R. W.; Harrell, C.
M.; Reiss, D. R.; Holahan, M. A.; Cook, J.; Hess, J. F.; Sain, N.; Urban, M. O.;
Tang, C.; Prueksaritanont, T.; Pettibone, D. J.; Bock, M. G. J. Med. Chem. 2007,
50, 272.
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a
a
Compd
t1/2
(h)
Cla
(mL/h/kg)
Vss
Oral
RLM
(lL/min/mg)
(mL/kg)
%Fb
1
15b
15k
1.2
1.5
2.4
1890
1834
1992
2952
3616
5860
13%
10%
15%
388
282
240
Dosed IV (1 mg kgÀ1) in DMSO.
a
Dosed PO (10 mg kgÀ1) in 2% HPMC/1% Tween 80 in water.
b
The SAR results on the allylic amine portion could be applied to
other scaffolds for further optimization.
12. Wood, M. R.; Kim, J. J.; Han, W.; Dorsey, B. D.; Homnick, C. F.; Dipardo, R. M.;
Kuduk, S. D.; MacNeil, T.; Murphy, K. L.; Lis, E. V.; Ransom, R. W.; Stump, G. L.;
Lynch, J. J.; O’Malley, S. S.; Miller, J.; Chen, T.-B.; Harrel, C. M.; Chang, R. S. L.;
Sandhu, P.; Ellis, J. D.; Bondiskey, J.; Pettibone, D. J.; Freidinger, R. M.; Bock, M.
G. J. Med. Chem. 2003, 46, 1803.
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O’Malley, S. S.; Ransom, R. W.; Chang, R. S. L.; Ha, S.; Hess, F. J.; Pettibone, D. J.;
Mason, G. S.; Boyce, S.; Freidinger, R. M.; Bock, M. G. J. Am. Chem. Soc. 2003, 125,
7516.
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