Novel small molecule bradykinin B2 receptor antagonists

Article abstract of DOI:10.1021/jm9002445

Blockade of the bradykinin B₂ receptor provides therapeutic benefit in hereditary angioedema (HAE) and potentially in many other diseases. Herein, we describe the development of highly potent B₂ receptor antagonists with a molecular weight of approximately 500 g/mol. First, known quinoline-based B₂ receptor antagonists were stripped down to their shared core motif 53, which turned out to be the minimum pharmacophore. Targeted modifications of 53 resulted in the highly water-soluble lead compound 8a. Extensive exploration of its structure-activity relationship resulted in a series of highly potent B₂ receptor antagonists, featuring a hydrogen bond accepting functionality, which presumably interacts with the side chain of Asn-107 of the B₂ receptor. Optimization of the microsomal stability and cytochrome P450 inhibition eventually led to the discovery of the highly potent and orally available B₂ receptor antagonist 52e (JSM10292), which showed the best overall properties.

Full text of DOI:10.1021/jm9002445

4370 J. Med. Chem. 2009, 52, 4370–4379
DOI: 10.1021/jm9002445
Novel Small Molecule Bradykinin B2 Receptor Antagonists
Christoph Gibson,*,† Karsten Schnatbaum,† Jochen R. Pfeifer,† Elsa Locardi,† Matthias Paschke,‡ Ulf Reimer,§ Uwe Richter,§
Dirk Scharn, Alexander Faussner,^ and Thomas Tradler‡
†Jerini AG, Department of Medicinal Chemistry, Invalidenstrasse 130, Berlin, D-10115 Germany, ‡Jerini AG, Department of Lead Discovery
Biology, Invalidenstrasse 130, Berlin, D-10115 Germany, §Jerini AG, Department of Computational Chemistry, Invalidenstrasse 130, Berlin,
D-10115 Germany, Jerini AG, Department of DMPK & Analytics, Invalidenstrasse 130, Berlin, D-10115 Germany, and ^Ludwig-Maximilians-
Universtat Munchen, Abteilung fur Klinische Chemie und Klinische Biochemie, Nussbaumstrasse 20, D-80336 Munchen, Germany
Received February 26, 2009
Blockade of the bradykinin B2 receptor provides therapeutic benefit in hereditary angioedema (HAE)
and potentially in many other diseases. Herein, we describe the development of highly potent B2 receptor
antagonists with a molecular weight of approximately 500 g/mol. First, known quinoline-based B2
receptor antagonists were stripped down to their shared core motif 53, which turned out to be the
minimum pharmacophore. Targeted modifications of 53 resulted in the highly water-soluble lead
compound 8a. Extensive exploration of its structure-activity relationship resulted in a series of highly
potent B2 receptor antagonists, featuring a hydrogen bond accepting functionality, which presumably
interacts with the side chain of Asn-107 of the B2 receptor. Optimization of the microsomal stability and
cytochrome P450 inhibition eventually led to the discovery of the highly potent and orally available B2
receptor antagonist 52e (JSM10292), which showed the best overall properties.
Introduction
shown that the blockade of the B2 receptor may provide
therapeutic benefit in pathological conditions such as asth-
ma,6 allergic rhinitis,6b,7 pancreatitis,8 osteoarthritis,9 trau-
matic brain injury,10 Alzheimer’s disease,11 and angioedema.12
However, for the sake of completeness, itshould be mentioned
that bradykinin as a compensatory vasodilator may also have
a salutary effect in certain clinical situations.13 Recently, in
clinical trials, the highly specific B2 receptor antagonist icati-
bant14 proved to be efficacious in treating acute attacks of
hereditary angioedema and thus demonstrated the therapeu-
tic potential of B2 receptor antagonists.15
Since 1985, a number of peptide B2 receptor antagonists
have been described, with the marketed drug icatibant being
the most prominent representative of this group. Since the
early 1990s, the drug discovery programs of many pharma-
ceutical companies resulted in the development of a diverse set
of nonpeptide B2 receptor antagonists.16 In particular, the
pioneering work of Fujisawa Pharmaceutical provided early
evidence for the druggability of the B2 receptor based on small
molecules. They described, in a series of publications and
patent applications, the transformation of a directed random
screening hit into a novel class of potent nonpeptide B2
receptor antagonists, including the orally available FK3657
(1)17 (Figure 1). In the following years, numerous patent
applications have been filed disclosing B2 receptor antagonists
featuring the 8-benzyloxy-2-methyl-quinoline motif of com-
pound 1. Representative structures of this class of compounds
are shown in Figure 1. Hoechst AG described close analogues
to compound 1 such as compound 2, however without
disclosing the activity at the human B2 receptor.18 Anatibant
(3), developed by Fournier, represents one of the most ad-
vanced small molecule B2 receptor antagonists, but no data
have been published demonstrating oral availability of this
compound.19 In January 2007, a phase II clinical trial for
The kinins bradykinin (BK;a H-Arg-Pro-Pro-Gly-Phe-Ser-
Pro-Phe-Arg-OH) and kallidin (KD; H-Lys-Arg-Pro-Pro-
Gly-Phe-Ser-Pro-Phe-Arg-OH) are oligopeptide hormones
generated as short-lived components of the kallikrein-kinin
system. The concentration of circulating kinins is maintained
at a low level under normal physiological conditions and may
be rapidly increased under pathological situations by the
enzymatic degradation of the circulating glycoprotein pre-
cursors called kininogens. The two most potent kininogen-
metabolizing enzymes are the trypsin-like serine proteases
plasma kallikrein and tissue kallikrein. The precursors of
these enzymes are normally present in all tissues and are ready
to be activated by physiological or pathophysiological pro-
cesses.1 Two cell surface receptors, B1 and B2, have been
classified, which mediate the cellular actions of kinins.2 Both
receptors are members of the seven transmembrane G-pro-
tein-coupled receptor (GPCR) superfamily.3 They were char-
acterized as endogenous and recombinant receptors in
pharmacological studies as well as by generation of knockout
mice.1c,4 B2 receptors are expressed constitutively in most cell
and tissue types and mediate most of the known effects of BK
and KD when these are produced in plasma or tissues.2a In
contrast to the B2 subtype, B1 receptors are expressed at very
low basal levels under physiological conditions and their
expression is upregulated after exposure to proinflammatory
or noxious stimuli.5 A large number of in vivo studies have
*To whom correspondence should be addressed. Phone: þ49-30-9 78
93-281. fax: þ49-30-9 78 93-105. E-mail: christoph.gibson@jerini.com.
a Abbreviations: BK, bradykinin; CAM, calcium mobilization; CYP,
cytochrome P450; GPCR, G-protein-coupled receptor; IC50, inhibition
constant for 50% inhibition; KD, kallidin; RLB, radio ligand binding;
SAR, structure-activity relationship.
r
pubs.acs.org/jmc
Published on Web 06/24/2009
2009 American Chemical Society

Article
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 14 4371
Scheme 1a
a Reagents and conditions: (a) X = Br: heterocycle, n-BuLi, THF,
-78 ꢀC, then ZnCl2, -40 ꢀC, then Pd2dba3, PPh3, 80 ꢀC; (b) X = Cl:
heterocycle, dioxane, 100 ꢀC; (c) Pd(PPh3)4, Na2CO3, dioxane/H2O,
100 ꢀC; (d) 3,5-dichloro-4-chloromethyl-pyridine (15), Cs2CO3, DMF, rt;
(e) bis(pinacolato)diborane, Pd(dppf)Cl2, KOAc, DMSO, 85 ꢀC.
mol. The discovery of the minimal pharmacophore, followed
by extensive exploration of its structure-activity relationship
(SAR) resulted in 52e (JSM10292), which proved to be a highly
active B2 receptor antagonist being orally available in rat.
Chemistry. The synthesis of 4-heteroaryl-substituted qui-
nolines featuring a dichloro pyridine core is depicted in
Scheme 1. The five-membered heterocycles were either
coupled as zincates to the 4-bromo quinoline 5b via Negishi
couplings (method a) or condensated with the 4-chloro
quinoline 5a (method b). The halogen substituted five-mem-
bered heterocycles were coupled with boronic acid 7 via
Suzuki couplings (method c). When necessary, the hetero-
cycles were employed protected by suitable protecting
groups and deprotected after the coupling to the quinoline.
Scheme 2 shows the synthesis of compounds with various
substituents in 3-position of the pyridine core. All syntheses
started from 10 or 11. The halogen atom of these building
blocks or analogues made out of them were substituted via a
variety of different reactions: nucleophilic displacement by
oxygen (method d) or sulfur (method q or p), Heck reaction
(method g), or halogen-metal exchange followed by for-
mylation (method i, Scheme 2). Further transformations
with standard methodology afforded compounds 38a-q.
Compounds containing a 4-methyl pyridine core structure
were synthesized according to Scheme 3. Carbonylation of
4-bromo-2-chloro-pyridine, selective methylation at the bro-
mine position, and subsequent standard transformations
afforded the benzylic chlorides 44, 47, and 48. Different
heterocycles were coupled to the 4-bromo quinoline core
via Negishi coupling methodology. Alkylation with the
previously synthesized benzylic chlorides yielded the desired
compounds 52a-e.
Figure 1. Selected small molecule B2 receptor antagonists featuring
the 8-benzyloxy-2-methyl-quinoline motif.
traumatic brain injury was initiated by Xytis using an inject-
able formulation of compound 3. Recently, Menarini de-
scribed a series of highly polar B2 receptor antagonists includ-
ing MEN16132 (4) dedicated for the treatment of airway
inflammatory pathologies.20 These compounds were opti-
mized for inhalation and show minimum systemic exposure
after intratracheal administration.
It is important to note that the average molecular weight of
the disclosed B2 receptor antagonists is rather high. In fact,
with a high molecular weight of 592.5 g/mol, compound 1
represents one of the smallest B2 receptor antagonist published
to date. As a consequence, most of these compounds feature
properties commonly considered as unfavorable with regards
to oral bioavailability such as a high number of rotatable
bonds and a large polar surface area. In this paper, we wish to
document the development of highly potent B2 receptor
antagonists with a molecular weight of approximately 500 g/
Results and Discussion
We decided to start our program with the exploration of
established quinoline-based B2 receptor antagonists, as ex-

4372 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 14
Gibson et al.
Scheme 2a
a Reagents and conditions: (a) NaBH4, EtOH, rt; (b) 3,4-dihydro-2H-pyran, pTsOH, DCM, rt; (c) SOCl2, catalytic quantity of H2O, DCM, rt;
(d) KOtBu, dioxane, 100 ꢀC; (e) ClCH2CON(CH3)2, Cs2CO3, THF, rt; (f) 6h, Cs2CO3, DMF, rt; (g) CH2dCHCONH2 or CH2dCHCON(CH3)2,
Pd(OAc)2, DIEA, P(oTol)3, DMF, 120 ꢀC; (h) NaBH4, MeOH, rt; (i) n-BuLi, ethylformate, -78 ꢀC f rt; (j) Ac2O, pyridine, rt or dimethylcarbamoyl
chloride, NaH, DMF, rt; (k) MsCl, NEt3, DCM, 0 ꢀC; (l) pyridone, Cs2CO3, DMF, rt; (m) DPPA, DBU, toluene, rt; (n) H2, Pd/C, MeOH, rt; (o) Cl-CO-
R6, aq NaHCO3, DCM, rt; (p) thiazole-2-thiol or 1-methyl-1H-imidazole-2-thiol, Cs2CO3, THF, rt; (q) NaSH, DMF, rt; (r) BrCH2CONH2 or
ClCH2CONMe2, NaHCO3, DMF, rt; (s) H2O2, HOAc, 50 ꢀC; (t) MsCl, Et3N, DCM, rt.
emplified in Figure 1. It was obvious, however, that the drug-
like properties of this class of antagonists were compromised
by their high molecular weight. Consequently, we were
focusing on the discovery of key pharmacophores that may
ultimately result in the design of downsized and highly active
B2 receptor antagonists. Theimplementationofthis strategyis
outlined in Figure 2. First, the quinoline-based B2 receptor
antagonists were stripped down to their shared core motif 53,
which turned out to be the minimum pharmacophore. Com-
pound 53 showed acceptable affinity to the B2 receptor as
determined in the radio ligand binding (RLB) assay, but
due to poor aqueous solubility of less than 1 μM, 53 was of
limited use as a lead compound. Inspired by the work of
Sawada et al., who showed thatthe activity of quinoline-based
B2 receptor antagonists can be improved by the introduction
of a five-membered heterocycle in the 4-postion of the quino-
line moiety,21 we decided to substitute 53 with a polar
imidazole ring in the corresponding position. In addition,
the phenyl ring was replacedbya pyridine ring, resulting in the
substantially more polar 8a. Because of its good aqueous
solubility of >50 μM, low molecular weight of 385 g/mol, and
respectable respectrable IC50 value of 580 nM in the RLB
assay, compound 8a was selected as the lead compound for
further modifications. Optimization of the five-membered

Article
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 14 4373
Scheme 3a
Figure 2. Outline of the optimization program resulting in the
highly active and orally available B2 receptor antagonist 52e.
assay based on specific binding of [3H]-BK to recombinant
human B2 receptor expressed in HEK293 cells and a BK-
mediated calcium mobilization (CAM) assay using HF-15
primary human fibroblasts. We discovered that the modest
binding affinity of the quinoline 9 could be improved by a
factor of up to 265 by the installation of an appropriate five-
membered heterocycle in the 4 position of the quinoline
moiety. A diverse set of unsubstituted heterocycles proved
to be tolerated by the B2 receptor such as the N-linked
imidazole ring (8a), the N-linked (8f) and the C3-linked (8g)
pyrazole ring as well as the thiazole ring (8m, 8n, and 8q). The
imidazole derivatives 8a-8e revealed the general SAR of the
five-membered heterocycles. The introduction of a methyl
group adjacent to the quinoline moiety (8b, 8d) usually
improved the binding affinity, while those antagonists featur-
ing an N-atom acceptor opposite to the methyl and quinoline
group (8c) lost appreciable affinity. An additional substituent
was tolerated vicinal to the methyl group (8e), although it
slightly negatively impacted the affinity. Installation of a
pyrazole ring (8f-8j) generally led to compounds with en-
hanced functional potency as compared to the imidazole
derivatives (8a-8e), and it was not unexpected that the
methylation of the N-atom of 8g adjacent to the quinoline
moiety resulted in an improved binding affinity (8h). The
C-methylated pyrazole 8i revealed a substantially higher bind-
ing affinity than the C-methylated pyrazole 8j, indicating that
the preferred tautomeric forms correlate with the structures
shown in Table 1. Hence 8i features an N-H opposite to the
methyl and quinoline group, resulting in a beneficial effect on
the binding affinity, whereas 8j features an N-atom acceptor
in this position resulting in an unfavorable receptor interac-
tion. This general trend was also observed in the triazole series
in which the methylated triazole 8k exhibited high binding
affinity, while shifting one N-atom to the critical position (8l)
was again not tolerated by the B2 receptor. Regarding the
binding affinity to the B2 receptor, the preferred attachment
a Reagents and conditions: (a) LDA, THF, -78 ꢀC, then methyl-
chloroformate, -78 ꢀC; (b) ZnMe2, Pd(dppf)Cl2, dioxane, 70 ꢀC;
(c) CuCN, NMP, 180 ꢀC; (d) DIBAL, AlCl3, THF, -95 ꢀC f 4 ꢀC;
(e) isobutyryl chloride, CH2Cl2, aq Na2CO3, rt; (f) SOCl2, CH2Cl2, rt;
(g) DIBAL, THF, -78 ꢀC f rt; (h) 3,4-dihydro-2H-pyran, pTsOH,
DCM, rt; (i) vinyl boronic acid anhydride pyridine complex, K2CO3,
Pd(PPh3)4, DME/H2O, 100 ꢀC; (j) O3, DCM, -50 ꢀC, 10 min, then NaBH4,
MeOH, -50 ꢀC f rt; (k) MsCl, NEt3, DCM, 0 ꢀC; (l) 3-trifluoromethyl-
pyridin-2-ol, Cs2CO3, DMF, rt; (m) Li, naphthalene, ZnCl2, THF,
-78 ꢀC f -40 ꢀC, then 4-bromo-8-(tert-butyl-dimethyl-silanyloxy)-2-
methyl-quinoline, Pd(PPh3)4, 70 ꢀC; (n) TBAF, THF, rt; (o) n-BuLi,
ZnCl2, THF, -78 ꢀC f -40 ꢀC, then 4-bromo-2-methyl-quinolin-8-ol,
Pd2dba3, PPh3, THF, 80 ꢀC; (p) Cs2CO3, DMF, rt.
heterocycle and subsequent exploration of pyridine substitu-
ents resulted in a series of highly potent B2 receptor antago-
nists such as the thiazolyl-thioether 38b, which benefits from
the formation of a hydrogen bond between its thiazole ring
and the side chain of Asn-107 of the B2 receptor (see below for
a detailed discussion of the Asn-107 interaction). The discov-
ery of this specific interaction eventually enabled the devel-
opment of the highly potent low molecular weight B2 receptor
antagonist 52e.
First, we were focusing on the optimization of the five-
membered heterocycle of lead compound 8a, which is shown
in Table 1. The in vitro activity was assessed in both a RLB

4374 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 14
Gibson et al.
Table 1. SAR of Five-Membered Heterocycle: Binding Affinity and Functional Activity of Compounds 9 and 8a-w on the B2 Receptora
a Values represent the numerical average of at least two experiments. b IC50 of specific binding of [3H]-BK to recombinant human B2 receptor
expressed in HEK293 cells. c IC50 of BK-mediated calcium mobilization in HF-15 primary human fibroblasts.
point for the unsubstituted thiazole ring (8m, 8n, and 8q) was
shown to be the 4C-position. In the case of both the 5C-linked
thiazole derivative (8o) and the 4C-linked thiazole derivative
(8r), the introduction of a methyl group adjacent to the
quinoline moiety only slightly improved the binding affinity.
Replacement of the methyl group with a chlorine atom
resulted in an approximate 9-fold loss in affinity of the 5C-
linked derivative (8p) and an approximate 3-fold loss in
affinity of the 4C-linked derivative (8s). Two methylated
isothiazole derivatives were found to show decent (8t) to
excellent (8u) binding affinity. However, replacement of the
sulfur atom of the thiazole and isothiazole rings with an
oxygen atom was not tolerated by the B2 receptor, as was
shown by the oxazole 8v and isoxazole 8w.
Because B2 antagonists with N-linked five-membered het-
erocycles proved to be moderately unstable under acidic
conditions due to hydrolysis of the five-membered hetero-
cycle-quinoline bond, we decided to abandon further explora-
tion of these compounds. Because of their good binding
affinity and good functional potency as well as due to their
superior liver microsomal stability, the N-methyl pyrazole
derivatives (8h) and 4C-methyl pyrazole derivatives (8i) were
chosen for further modifications. Although the chloro-thia-
zole 8s revealed only moderate functional potency, it was also
selected because preliminary metabolite identification studies
revealed that its chloro-thiazole ring was highly resistant to
microsomal degradation.
After the optimization of the five-membered heterocycle, we
directed our attention to the exploration of the pyridine SAR.
The corresponding phenyl cores of all previously reported
quinoline-based B2 receptor antagonists are characterized by a
large substituent in the meta position to the quinolinyloxy-
methyl moiety (Figure 1). We hypothesized that the structural
diversity found in this position indicates a lack of specific
receptor interaction that may preclude the development of a
small meta substituent with high binding affinity. As a result,
we decided to explore the alternative ortho position based on
the easily accessible N-methyl pyrazole derivatives. The results
of our efforts are shown in Table 2. In the lower nanomolar
range, the test compound concentration equals the B2 receptor
concentration of the RLB assay. This results in a limitation of
the validity of the corresponding IC50 values. With a B2
receptor concentration in the picomolar range, we considered
the CAM assay more reliable for the evaluation of highly
potent antagonists. Furthermore, in contrast to the RLB
assay, the CAM assay proved to be sensitive enough to
monitor ligand-mediated activation of endogenous B2 recep-
tors in human HF-15 foreskin fibroblasts. The ability to

Article
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 14 4375
Table 2. Binding Affinity and Functional Activity of Compounds 8h
and 38a-q on the B2 Receptora
synthesis and evaluation of an ortho thioether library revealed
that the installation of a hydrogen bond accepting function-
ality such as a thiazole (38b) or an imidazole ring (38c) led to
an enhanced functional potency. In the 4-imidazol-1-yl-qui-
noline series (data not shown), the thiazol-2-yl-thioether
derivative proved to be 9-fold more potent than the thio-
phene-2-yl-thioether analogue, which lacks the hydrogen
bond acceptor. Modeling studies involving the generation of
homology model ensembles for the B2 receptor and extensive
docking and optimization efforts could rationalize these
findings, suggesting the formation of a hydrogen bond be-
tween the side chain of asparagine 107 and the thiazole ring of
38b. The calculated binding model was supported by site-
directed mutagenesis experiments with the 4-imidazol-1-yl-
quinoline analogue of compound 38b. This compound com-
peted for the [3H]-BK binding site at the wild type B2 receptor
with an IC50 value of 470 nM and with an IC50 value of
2300 nM at the N107A mutant.
To eliminate the metabolically labile and potentially cyto-
chrome P450 (CYP)-inhibiting thioether-linked heterocycles,
a number of alternative hydrogen bond accepting functional-
ities were evaluated. It turned out that replacement of the
thioether-linked heterocycle with an appropriate thioether-
linked amide fragment maintained the functional potency
(38d). Mere replacement of the thioether group with a sulf-
oxide (38e), an ether (38f), or a methylene group (38g) resulted
in a significantly reduced functional potency. Compound 38h,
however, demonstrated with an excellent IC50 value of 2.3 nM
in the CAM assay that the combination of sulfur-methylene
exchange and nitrogen atom shift of the amide group leads to
an improved in vitro activity. Transformation of the amide
group of 38h into a urea group (38i) did not alter the
functional potency, whereas the corresponding carbamate
38j proved to be less potent. A general trend observed for
compounds in this series was that hydrophobic substituents
vicinal to the carbonyl group substantially improved func-
tional potency in the CAM assay while barely affecting
binding affinity in the RLB assay. This is exemplified by the
acetamide 38l, which was 10-fold less potentin the CAM assay
when compared to the isopropyl amide 38h. In this series, it
was shown that the replacement of the amide group with an
ester(38m)orsulfonamidegroup(38n)resultedina significant
reduced functional potency. We ultimately discovered that the
potency could be maintained by replacing the amide group
with a nitrogen-linked pyridone ring (38o), whose functional
potency could be further improved by the installation of a
CF3-group in ortho position to the carbonyl group (38q).
With a number of highly active B2 receptor antagonists in
hand, we focused on the optimization of microsomal stability
and CYP inhibition. In a series of structurally related analo-
gues of the compounds shown in Table 2, we observed that
shifting the nitrogen atom of the pyridine core in para position
to the chlorine atom positively impacted both microsomal
stability and CYP inhibition. However, para-chloro-pyridine
derivatives are usually prone to nucleophilic substitution
reactions, and we observed a substantial improvement of
the water solubility by switching from the chlorine to the
methyl group, which prompted us to choose the para-methyl
pyridine analogues for further optimization (Table 3).
a Values represent the numerical average of at least two experiments.
b IC50 of specific binding of [3H]-BK to recombinant human B2 receptor
expressed in HEK293 cells. c IC50 of BK-mediated calcium mobilization
in HF-15 primary human fibroblasts.
measure endogenous B2 receptors seems particularly attractive
for the generation of SAR and the selection of a drug
candidate, as it enables to employ the B2 receptor in its native
environment. Thus, at this stage of the project, we decided to
have the optimization of the potent advanced lead compounds
guided by the CAM assay. Because all tested compounds were
isolated as colorless solids, they are not likely to cause non-
specific optical interactions in the CAM assay.
Substitution of the hydrogen atom with a chlorine atom in
ortho position to the quinolinyloxymethyl moiety of 38a
improved the activity by a factor of 10 (8h), presumably due
to a hydrophobic interaction with the B2 receptor. The
The SAR of the para-methyl-pyridine derivatives proved to
be fairly consistent with that of the meta-chloro-pyridine
derivatives. Excellent potency was achieved by installation
of a hydrophobic moiety adjacent to the carbonyl group as
exemplified by the N-methyl pyrazole analogues 52a, 52b, and

4376 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 14
Gibson et al.
Table 3. Binding Affinity and Functional Activity of Compounds
52a-e on the B2 Receptora
Experimental Section
Chemistry (General). All commercially available solvents and
reagents were used without further treatment as received unless
otherwise noted. All reactions were stirred magnetically; moisture-
sensitive reactions were performed under argon in heatgundried
glassware. For analytical TLC, Merck silica gel 60 F254 plates
were used and column chromatography was performed on
Merck silica gel 60 (0.015-0.040 mm). All tested compounds
were analyzed by HPLC-MS on a Surveyor HPLC combined
with an LCQ classic or Advantage (all Thermo Electron, US)
equipped with an ESI-source and showed a purity of >95%. 1H
NMR spectra were measured in ACN-D3, CDCl3, or DMSO-
d6 with a Varian 500 MHz spectrometer; chemical shifts are
expressed in ppm relative to TMS as internal standard and
coupling constants (J) in Hz.
Synthesis of 3,5-Dichloro-4-chloromethyl-pyridine (15).
NaBH4 (0.838 g, 22.2 mmol) was added to a stirred solution
of 3,5-dichloro-pyridine-4-carbaldehyde (3.0 g, 17 mmol) in
ethanol (40 mL). After stirring for 35 min at room temperature,
the reaction mixture was concentrated in vacuo, and the residue
was redissolved in ethyl acetate (200 mL) and washed with water
(50 mL). The organic layer was dried over Na2SO4, filtered, and
concentrated in vacuo to give (3,5-dichloro-pyridin-4-yl)-
methanol (2.83 g, 94%), which was used in the next step without
purification. MS (m/z): 178.1 [M þ Hþ].
a Values represent the numerical average of at least two experiments.
b IC50 of specific binding of [3H]-BK to recombinant human B2 receptor
expressed in HEK293 cells. c IC50 of BK-mediated calcium mobilization
in HF-15 primary human fibroblasts.
52c. The trifluoromethyl-substituted pyridone 52c revealed
the highest potency as well as the highest human microsomal
stability in this series. Preliminary metabolite identifica-
tion studies based on the incubation with liver microsomes
identified the N-methyl pyrazole group as a major metabolic
soft spot, which turned out to be prone to metabolic demethy-
lation. We therefore decided to discontinue further explora-
tion of N-methylated five-membered heterocyle analogues.
Good microsomal stability and high potency was eventually
achieved by the combination of the CF3-pyridone-substituted
framework with a chloro-thiazole ring (52d) or a C-methyl
pyrazole ring (52e). With 34% remaining parent compound
after 30 min incubation in the liver microsome assay, the
chloro-thiazole analogue 52d proved to be slightly superior to
the C-methyl pyrazole analogue 52e, which showed 21%
remaining of parent compound in the same assay. However,
in contrast to 52e, 52d was found to be a potent inhibitor of
CYP2C19 (IC50 = 0.3 μM), which caused us to select 52e for a
more comprehensive profiling. Compound 52e displayed
neutral antagonist activity in the CAM assay and featured
no partial agonistic activity up to the highest tested concen-
tration of 5 μM. Preliminary pharmacokinetic studies in
female Wistar rats showed that 52e features low clearance
SOCl2 (2.3 mL, 32 mmol) was added dropwise to a stirred
solution of (3,5-dichloro-pyridin-4-yl)-methanol (2.83 g,
15.9 mmol) in DCM (20 mL) over 10 min. After stirring for 35
min at room temperature, saturated aqueous Na2CO3 solution
(40 mL), and DCM (60 mL) was added to the reaction mixture.
The organic layer was dried over Na2SO4, filtered, and concen-
trated in vacuo. The residue was purified by flash chromatog-
raphy on silica gel (elution with EA/hexane 1:4) to give the title
compound (15) (2.65 g, 85%). MS (m/z): 196.0 [M þ Hþ].
Synthesis of 8-(3,5-Dichloro-pyridin-4-ylmethoxy)-2-methyl-
quinoline (9). Cs2CO3 (261 mg, 0.8 mmol) was added to a
vigorously stirred solution of 3,5-dichloro-4-chloromethyl-pyri-
dine (15) (48 mg, 0.24 mmol) and 2-methyl-quinolin-8-ol
(32 mg, 0.2 mmol) in DMF (1 mL). After stirring for 18 h at
room temperature, the solvent was removed in vacuo. The residue
was purified by reversed phase HPLC using a gradient of acet-
onitrile in water with 0.1% TFA to give the title compound (280
mg, 65%) as the TFA salt. 1H NMR (500 MHz, ACN-d3): δ =
8.66 (d, J = 8.1 Hz, 1H), 8.43 (s, 2H), 7.79 (t, J =Hz, 1H), 7.75-
7.61 (m, 3H), 5.47 (s, 2H), 2.80 (s, 2H). MS (m/z): 319.0 [M þ Hþ].
Synthesis of 2-Methyl-4-(1-methyl-1H-imidazol-2-yl)-quino-
lin-8-ol (6d). n-Butyllithium (1.6 M in hexane, 6.0 mL, 9.7 mmol)
was added dropwise to a stirred solution of 1-methyl-1H-
imidazole (0.83 mL, 11 mmol) in anhydrous THF (60 mL) at
-87 ꢀC. The reaction mixture was allowed to warm to -40 ꢀC. A
solution of ZnCl2 (3.9 g, 28 mmol) in anhydrous THF (28 mL)
was than added dropwise at -78 ꢀC. The reaction mixture was
allowed to reach room temperature and was than transferred to
a suspension of Pd(PPh4)4 (340 mg, 0.29 mmol) and 4-bromo-2-
methyl-quinolin-8-ol (5b) (1.0 g, 4.2 mmol) in anhydrous diox-
ane (20 mL). After stirring for 90 min at 80 ꢀC, the reaction
mixture was cooled to room temperature, MeOH (5 mL) was
added, and the solvent was removed in vacuo. The residue was
partitioned between DCM (150 mL) and water (50 mL). The pH
of the aqueous layer was adjusted to 11 by the addition of
concentrated aqueous NH3 solution, and the aqueous layer was
extracted with DCM (2 ꢀ 100 mL). The combined organic layers
were dried over Na2SO4, filtered, and concentrated in vacuo.
The residue was purified by flash chromatography on silica
gel (elution with DCM/MeOH 20:1) to give the title compound
6d (614 mg, 61%). 1H NMR (500 MHz, DMSO-d6): δ = 7.53 (s,
1H), 7.42 (s, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.31 (d, J = 7.5 Hz,
1H), 7.15 (d, J = 1.5 Hz, 1H), 7.09 (dd, J = 7.3, 1.5 Hz, 1H), 3.58
(s, 3H), 2.75 (s, 3H). MS (m/z): 240.2 [M þ Hþ].
(CL = 21 mL/(min kg), good terminal half-life (67 min), and
substantial oral bioavailability (F > 17%).22
3
Conclusions
In this study, we demonstrated the feasibility of the devel-
opment of highly potent quinoline-based B2 receptor antago-
nists featuring a lowmolecular weight of approximately 500 g/
mol. By systematic downsizing of known B2 antagonists, we
identified theminimumpharmacophore53, which was usedas
the starting point for our extensive SAR studies. The installa-
tion of a hydrogen bond accepting functionality at the pyr-
idine ring enabled a significant enhancement of the functional
potency with only minor increase in molecular weight. In this
series, the highly potent and orally available B2 antagonist 52e
revealed the best overall properties. Further characterization
and complete pharmacological profile of 52e will be published
shortly.

Article
Synthesis of 8-(3,5-Dichloro-pyridin-4-ylmethoxy)-2-methyl-
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 14 4377
A solution of chloro-pyridine 42 (500 mg, 2.07 mmol), vinyl
boronic acid anhydride pyridine complex (498 mg, 2.07 mmol),
K2CO3 (286 mg, 2.07 mmol) in DME (16.5 mL), and water
(7 mL) was deoxygenated before Pd(PPh3)4 (120 mg, 0.10 mmol)
was added. The reaction was heated to 100 ꢀC and stirred at this
temperature for 20 h, cooled to rt, and concentrated in vacuo.
The residue was purified by flash chromatography on silica gel
(elution with hexane/EtOAc 6:1 f 4:1) to give 4-methyl-3-
(tetrahydro-pyran-2-yloxymethyl)-2-vinyl-pyridine (432 mg,
89%). MS (m/z): 195.0 GC/MS [Mþ].
4-(1-methyl-1H-imidazol-2-yl)-quinoline (8d). Quinoline 6d
(16 mg, 67 μmol) was reacted with 3,5-dichloro-4-chloro-
methyl-pyridine (13 mg, 67 μmol) (15) as described for the
synthesis of 9. Purification by reversed phase HPLC using a
gradient of acetonitrile in water with 0.1% TFA yielded the title
compound 8d (6.9 mg, 20%) as a TFA salt. MS (m/z): 399.2
[M þ Hþ]. 1H NMR (DMSO-d6): δ = 8.79 (s, 2H), 7.97 (s, 1H),
7.92 (s, 1H), 7.84 (s, 1H), 7.62 (t, J = 8.1 Hz, 1H), 7.56 (d, J =
7.3 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 5.52 (s, 2H), 3.70 (s, 3H),
2.72 (s, 3H).
A solution of vinyl pyridine 4-methyl-3-(tetrahydro-pyran-2-
yloxymethyl)-2-vinyl-pyridine (300 mg, 1.29 mmol) in DCM
(36 mL) was cooled to -50 ꢀC, and a stream of ozone was
bubbled through it until the color of the reaction mixture
changed to light blue. Sodium borohydride (486 mg, 12.9 mmol)
was suspended in MeOH (15 mL) and immediately added to the
ozonide solution. The reaction mixture was warmed to room
temperature (1 h). After checking that all ozonides had been
destroyed by means of iodine starch paper, solvents were
removed in vacuo. The residue was partioned between water
and DCM was extracted with CH2Cl2 (3 ꢀ 20 mL). The organic
layers were dried over Na2SO4, filtered, and concentrated in
vacuo. Purification by flash chromatography on silica gel (elu-
tion with DCM/MeOH 40:1 f 20:1) delivered the alcohol 43
(254 mg, 1.23 mmol, 83%). MS (m/z): 476.0 [M þ Hþ].
Synthesis of 1-(3-Chloromethyl-4-methyl-pyridin-2-ylmethyl)-
3-trifluoromethyl-1H-pyridin-2-one (44). Alcohol 43 (36 mg,
0.15 mmol) and NEt3 (63 μL, 0.45 mmol) were dissolved in THF
(1 mL), and methanesulfonyl chloride (13 μL, 0.17 mmol) was
added. The reaction mixture was stirred for 10 min at rt before
the solvents were removed in vacuo. The residue was dissolved in
DMF (0.35 mL) and added dropwise to a stirred suspension of
3-trifluoromethyl-pyridin-2-ol (24 mg, 0.15 mmol) and Cs2CO3
(49 mg, 0.15 mmol) in DMF (0.40 mL). After stirring for 2 h at
rt, sat. NaHCO3 (2 mL) was added. The mixture was extracted with
DCM (2 ꢀ 10 mL), dried over Na2SO4, filtered, and concentrated in
vacuo. Purification by flash chromatography on silica gel (elution
with hexane/EtOAc 2:1 f 1:1) yielded 1-[4-methyl-3-(tetrahydro-
pyran-2-yloxymethyl)-pyridin-2-ylmethyl]-3-trifluoromethyl-1H-
pyridin-2-one (21 mg, 37%). MS (m/z): 382.8 [M þ Hþ].
1-[4-Methyl-3-(tetrahydro-pyran-2-yloxymethyl)-pyridin-2-
ylmethyl]-3-trifluoromethyl-1H-pyridin-2-one (21 mg, 54.9 μmol)
could be directly converted into the chloride 44 according to
the procedure described for the synthesis of 15, and it was used
in the next step without further purification. MS (m/z): 317.1
[M þ Hþ].
Synthesis of 8-(3,5-Dichloro-pyridin-4-ylmethoxy)-2-methyl-
4-(4-methyl-2H-pyrazol-3-yl)-quinoline (8i). 4-Methyl-1H-pyra-
zole (0.8 mL, 9.94 mmol) was dissolved in 4 mL DMF, and
BOM-Cl (1.5 mL, content of 60%, 5.0 mmol) was added at 0 ꢀC.
The reaction mixture was stirred for 45 min at rt and then was
quenched with 1 mL of aq NH3. The solvents were removed in
vacuo, and the residue was partitioned between water and DCM
and extracted with DCM (3 ꢀ 20 mL). The combined organic
layers were dried over Na2SO4, filtered, and concentrated in
vacuo. The residue was purified by flash chromatography on
silica gel (elution with DCM/methanol 20:1) gave 1-benzylox-
ymethyl-4-methyl-1H-pyrazole (1.36 g, 68%). 1H NMR
(DMSO-d6): δ = 7.67 (s, 1H), 7.37-7.26 (m, 6H), 5.42 (s,
2H), 4.48 (s, 2H). MS (m/z): 203.0 [M þ Hþ].
1-Benzyloxymethyl-4-methyl-1H-pyrazole (191 mg, 0.95
mmol) was coupled with 4-bromo-2-methyl-quinolin-8-ol (5b)
(75 mg, 0.32 mmol) according to the procedure described for
the synthesis of 6d. Purification by flash chromatography on
silica gel (elution with DCM/EtOAc 20:1) gave the BOM-
protected quinoline derivative 6i (99.8 mg, 87%). MS (m/z):
360.3 [MþHþ].
Quinoline 6i (47 mg, 131 μmol) was reacted with 3,5-dichloro-
4-chloromethyl-pyridine (15) (28 mg, 146 μmol) as described for
the synthesis of 9. Purification by reversed phase HPLC using a
gradient of acetonitrile in water with 0.1% TFA yielded the
BOM-protected title compound (5.5 mg, 5%) as a TFA salt. MS
(m/z): 399.2 [M þ Hþ]. This compound (5.5 mg, 6.4 μmol) was
dissolved in a mixture of 1.4 mL of TFA and 150 μL of DCM.
The reaction mixture was stirred at 80 ꢀC for 2 h and concen-
trated in vacuo. Purification by reversed phase HPLC using a
gradient of acetonitrile in water with 0.1% TFA yielded the title
compound 8i (2.1 mg, 44%) as the TFA salt. 1H NMR (DMSO-
d6): δ 8.78 (s, 2H), 7.80-7.42 (m, 5H), 5.52 (s, 2H), 2.71 (br s,
3H), 2.01 (br s, 3H). MS (m/z): 399.1 [M þ Hþ].
Synthesis of [4-Methyl-3-(tetrahydro-pyran-2-yloxymethyl)-
pyridin-2-yl]-methanol (43). Pyridine carboxylic ester 41 (300 mg,
1.62 mmol) was dissolved in THF (3 mL) and cooled to -78 ꢀC
before DIBAL-H (1.5 M in toluene, 3.2 mL, 4.86 mmol) was added
dropwise. The reaction mixture was allowed to warm to -20 ꢀCover
a period of 2 h. DIBAL-H (1.1 mL, 1.62 mmol) was added and
stirring was continued for 16 h (-20 ꢀC to rt). The reaction mixture
was then quenched by the addition of water (0.30 mL) at -20 ꢀC.
ACN (22 mL) and concentrated aqueous NH3 (1.8 mL) was added
to the mixture. After vigorous stirring for 30 min, the suspension
was centrifuged and the precipitate suspended in a solution of ACN
(6.5 mL) and concentrated aqueous NH3 (0.8 mL). After vigorous
stirring for 30 min, the suspension was centrifuged. The combined
supernatants were concentrated in vacuo to give the alcohol
(2-chloro-4-methyl-pyridin-3-yl)-methanol (266 mg, 104%), which
was used in the next step without further purification. MS (m/z):
158.1 [M þ Hþ].
Synthesis of 1-{4-Methyl-3-[2-methyl-4-(4-methyl-2H-pyrazol-
3-yl)-quinolin-8-yloxymethyl]-pyridin-2-ylmethyl}-3-trifluoromethyl-
1H-pyridin-2-one (52e). 4-Methyl-1H-pyrazole (550 mg, 6.7 mmol)
was dried by coevacuation with toluene. Pyridinium p-toluenesul-
fonate (168 mg, 0.67 mmol), DCM (30 mL), and 3,4-dihydro-2H-
pyran (1.82 mL, 20.1 mmol) were added and the reaction stirred
at 55 ꢀC for 16 h. After concentration in vacuo, the residue
was purified by flash chromatography on silica gel using a gradient
of hexane and EtOAc to give 49 (1.09 g, 98%). MS (m/z): 166.8
[M þ Hþ].
2-Methyl-4-[4-methyl-2-(tetrahydro-pyran-2-yl)-2H-pyrazol-
3-yl]-quinolin-8-ol (6i) was prepared from 4-bromo-2-methyl-
quinolin-8-ol (302 mg, 1.277 mmol) and pyrazole 49 (530 mg,
3.20 mmol) according to the procedure described for the synth-
esis of 6d. Purification by flash chromatography on silica gel
(elution with DCM/methanol 20:1) gave the quinoline deriva-
tive 6i (392 mg, 95%). MS (m/z): 324.0 [M þ Hþ].
Alcohol (2-chloro-4-methyl-pyridin-3-yl)-methanol (266 mg,
1.62 mmol) was dissolved in DCM (10 mL) and 3,4-dihydro-2H-
pyran (0.22 mL, 2.4 mmol) and para-toluene sulfonic acid
(0.37 g, 1.9 mmol) were added and the reaction mixture was
stirred for 1 h at rt. After removal of the solvent in vacuo, the
residue was purified by flash chromatography on silica gel with
DCM/EtOAc (40:1 f 30:1 f 20:1) to provide the pyridine
derivative 42 (276 mg, 71%). MS (m/z): 242.0 [M þ Hþ].
Chloride 44 (1.00 g, 3.16 mmol) was reacted with quinoline 6i
(1.12 g, 3.48 mmol) as described for the synthesis of 9. Purifica-
tion by flash chromatography on silica gel (elution with DCM/
MeOH 20:1 f 10:1) delivered 54 (2.02 g, 106%). MS (m/z):
604.2 [M þ Hþ].
Quinoline 54 (2.02 g, 3.34 mmol) was dissolved in MeOH
(25 mL) and concentrated aq HCl (2.5 mL) was added. After

4378 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 14
Gibson et al.
stirring for 30 min, the solvents were removed in vacuo and the
residue was purified by reversed phase HPLC using a gradient of
acetonitrile in water with 0.1% TFA to give the title compound
52e (1.16 g, 40%) as the TFA salt. 1H NMR (500 MHz, DMSO-
d6): δ 8.42 (d, J = 5.0 Hz, 1H), 8.13 (dd, J = 6.6, 1.6 Hz, 1H),
8.11-7.81 (m, 4H), 7.36 (d, J = 5.0 Hz, 1H), 6.43 (t, J = 7.2 Hz,
1H), 5.69 (s, 2H), 5.47 (s, 2H), 2.96 (br. s, 3H), 2.53 (s, 3H), 2.14
(s, 3H). MS (m/z): 520.1 [M þ Hþ].
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Acknowledgment. We thank Lena von Oertzen, Dagmar
Riexinger, Rocco Weise, Stephanie Koepke, Katy Pesta, Nicole
Liebelt, Bianka Knopp, Daniela Wulf, Daniel Herrmann,
Nadine Muller, and Maren Schlief for technical assistance.
HF15 human primary fibroblast cells were kindly provided by
Prof. Dr. Roscher (University Hospital of Munich).
Supporting Information Available: Experimental procedures,
characterization of new compounds, radioligand binding assay,
calcium mobilization assay, PK studies (general), microsomal
stability assay, CYP inhibition assay, and details of molecular
modeling. This material is available free of charge via the
Internet at http://pubs.acs.org.
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