Synthesis and structure-activity relationships of aroylpyrrole alkylamide bradykinin (B2) antagonists

Article abstract of DOI:10.1016/S0960-894X(03)00104-5

The synthesis and structure-activity relationships of a novel series of aroylpyrrole alkylamides as potent selective bradykinin B₂ receptor antagonists are described. Several members of this series display nanomolar affinity at the B₂ receptor and show activity in an animal model of antinociception.

Full text of DOI:10.1016/S0960-894X(03)00104-5

Bioorganic & MedicinalChemistry Letters 13 (2003) 1341–1344
Synthesis and Structure–Activity Relationships of Aroylpyrrole
Alkylamide Bradykinin (B2) Antagonists
Mark A. Youngman, John R. Carson, Jung S. Lee, Scott L. Dax, Sui-Po Zhang,
Ray W. Colburn, Dennis J. Stone, Ellen E. Codd and Michele C. Jetter*
Johnson & Johnson Pharmaceutical Research and Development, Welsh & McKean Roads, PO Box 776,
SpringHouse, PA 19477-0776, USA
Received 11 October 2002; accepted 8 January 2003
Abstract—The synthesis and structure–activity relationships of a novel series of aroylpyrrole alkylamides as potent selective brady-
kinin B2 receptor antagonists are described. Several members of this series display nanomolar affinity at the B2 receptor and show
activity in an animalmodelof antinociception.
# 2003 Elsevier Science Ltd. All rights reserved.
Bradykinin is an endogenous nonapeptide that plays an
important role in a variety of inflammatory diseases and
pain states.1 Bradykinin (BK) and the decapeptide kalli-
din are released from plasma and tissue protein kinino-
gens by the proteolytic action of kallikreins. These
peptides cause pain by stimulating nociceptors (C and Ad
fibers) through their action upon distinct G-protein cou-
pled receptors subtypes, B1 and B2.2 Bradykinin is among
the most potent of known algesic substances and there-
fore small-molecule bradykinin receptor antagonists may
be usefulin the treatment of various pain states. 3
Fujisawa series. Such a strategy could lead to com-
pounds with improved solubility, metabolic stability
and in vivo properties. As reported herein, we have
synthesized a series of aroylpyrrole alkylamides (e.g.,
Fig. 2) that possess nanomolar binding affinity for the
human B2 receptor, and display activity in an in vivo
modelof antinociception.
Our generalsynthetic approach was centered upon the
propensity of the pyrrole ring system to undergo facile
A variety of B2 antagonists has been reported but most
have been peptides and peptide mimetics.4,5 However,
more recently, several novel classes of non-peptide bra-
dykinin B2 receptor antagonists have been disclosed;
among them, a series of potent antagonists exemplified
by Fujisawa FR173657 (Fig. 1).6ꢀ8 Studies by Fujisawa
indicate that 2,6-disubstitution of the centralphenyl
ring, along with the N-methylacetamide were necessary
for binding to the human BK2 receptor. The role of the
unsaturated amide group was presumably electrostatic,
possibly contributing to interaction with the BK2
receptor as a hydrogen bond donor.9
Figure 1. Structure of FR 173657.
We attempted to design and synthesize novelbradyki-
nin antagonists in which pyrrolyl ring systems could
serve as replacements for amide linkages found in the
*Corresponding author. Tel.: +1-215-540-4873; fax: +1-215-628-
4985; e-mail: mjetter@prdus.jnj.com
Figure 2. Aroylpyrrole alkylamide B2 antagonist.
0960-894X/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0960-894X(03)00104-5

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M. A. Youngman et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1341–1344
and often predictable acylation. The route to 2,5-di-
substituted pyrrolyl congeners (entries 1–21) is shown
below. Thermal acylation of N-methyl-pyrrole-2-
methylacetate with various acyl chlorides10 followed by
saponification yielded the corresponding carboxylic
acids. Reaction with oxalyl chloride at low temperature
afforded acyl chlorides that were immediately reacted
with the anilino intermediates to construct the target
compounds. The anilino intermediates were prepared by
modification of known procedures (Scheme 1).11
Compounds containing N-alkylated pyrroles (entries
26–29) were obtained by condensation of alkyl amines
with dimethoxytetrahydrofuran and then elaboration
via a carbenoid reaction with ethyldiazoacetate in the
presence of copper bronze.12 This chemistry produced
2,5-disubstituted N-alkyl pyrrole esters along with
minor amounts of isomeric 3,5 N-alkyl pyrrole esters
which were separable by flash chromatography. As pre-
viously described, saponification, acid chloride forma-
tion followed by coupling to the aniline gave final
products (Scheme 2).
Scheme 3. (i) TFAA, CHCl3; (ii) NaH, R2X, DMF; (iii) NaBH4,
MeOH; (iv) cat DMAP, DCM.
Compounds lacking an alkyl substituent on the pyrrole
nitrogen center were prepared by generating a pyrrolyl
Grignard reagent followed by acylation with an appro-
priate Vilsmeier–Haack reagent to yield the t-butyl
ester.13 The ester was taken on in the usualfashion to
give the target compound (entry 30) (Scheme 4).
Substitution on the aniline nitrogen center was achieved
by trifluoroacetylation followed by alkylation using
sodium hydride and an alkyl halide. Trifluoroacetamide
cleavage was accomplished by reaction with sodium
borohydride in methanolto yiedl the N-alkyl aniline.
The N-alkyl anilines were then elaborated to the final
targets (entries 23–25) (Scheme 3).
Wittig homologation of the N-methylpyrroel carbox-
aldehyde produced the unsaturated propionate. Hydro-
genation and standard methods afforded 2,5-
disubstituted (pyrrolyl)propionic acids that were cou-
pled to the anilino intermediates to give the pyrrole
propionamide homologues (Table 2, entries 31–38)
(Scheme 5).
The binding affinities for a series of pyrroylalkylamides
at the B2 receptor are shown in Table 1.14 Compounds
were also evaluated in a GTPgS assay to determine their
15
functionalactivity (data not shown).
As anticipated due to structuralsimilarities, a portion of
the structure–activity relationships (SARs) of our series
paralleled that reported by Fujisawa. For example, the
anilino N-substituent was found to be crucialfor bind-
ing affinity (entry 22); alkyl groups larger than methyl
(entries 23–25) diminished binding affinity, in support of
Scheme 1. (i) R4COCl, toluene, heat; (ii) LiOH, THF/H2O; (iii)
(COCl)2, cat DMF, DCM, 0 ꢁC; (iv) A (R1=Cl) or B (R 1=Me), cat
DMAP, DCM.
Scheme 4. (i) BrCH2CO2t-Bu, EtMgBr, THF, ꢀ10 ꢁC to rt; (ii)
R4C(Cl)=NMe+2 Clꢀ, DCM; (iii) aq NaOAc; (iv) TFA/DCM; (v)
(COCl)2, cat DMF, DCM, 0 ꢁC; (vi) A or B, cat DMAP, DCM.
Scheme 2. (i) R3NH2, HOAc, heat; (ii) N2¼CHCO2Et, Cu(bronze),
heat; (iii) R4COCl, toluene, heat; (iv) LiOH, THF/H2O; (v) (COCl)2,
cat DMF, DCM, 0 ꢁC; (vi) A or B, cat DMAP, DCM.
Scheme 5. (i) Ph3P=CHCO2Et, benzene; (ii) H2, Pd/C, EtOH; (iii)
R4COCl, toluene, heat; (iv) LiOH, THF/H2O; (v) (COCl)2, cat DMF,
DCM, 0 ꢁC; (vi) A or B, cat DMAP, DCM.

M. A. Youngman et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1341–1344
1343
Table 1. Binding affinities at the B2 receptor
Table 3. Antinociceptive evaluation of pyrrolyl alkylamide analogues
in the Graded AbdominalIrritant (kaoiln) Test
Entry
R1
R2
R3
R4
Ki (nM)
Entry
R1
n
R4
ED50 (mmol/kg, po)
1
2
3
4
5
6
7
8
Cl
Me
Me
Me
t-Butyl1710
ClMe
ClMe
ClMe
ClMe
ClMe
ClMe
ClMe
ClMe
ClMe
ClMe
ClMe
ClMe
ClMe
ClMe
ClMe
Me
ClMe
Me
ClMe
Me
ClH
ClEt
Cl
Cl
ohCeyxcyll 1790
Ph
CH
)P(4h-Cl
(4-CF
(4-CONMe
(4-OMe)Ph
(4-SO
(4-SO
(4-NH
17
21
19
18
37
Me
Me
Me
Cl1
Cl2
1
1
1
(4-CN) Ph
(6-CN) 3-Pyr
(6-Cl) 3-Pyr
61
114
81
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
2290
92
2Ph
752
3)Ph
2)Ph
2370
) 3(-6P-yCrl
) 3(-6P-yCrl
69
23
476
204
9
2Me)Ph
2NH2)Ph
2)Ph
34
76
300
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
contrast to the anilino N-substituent, replacement of the
pyrrolyl N-methylgroup with other aklylgroups had
little effect on the binding affinity and even a group as
large as i-amylretained activity. In addition, anaol gues
that lacked substitution on the pyrrole nitrogen center
were also potent binders (entry 30).
(2-NHAc)Ph
(3-NHAc)Ph
(4-NHAc)Ph
2-Thienyl
869
73
57
239
(4-CN)Ph
23
Me
Me
Me
Me
Me
Me
(4-CN)Ph
69
Me
Me
)3(-6P-Cyrlidyl 121
Analogues containing simple alkyl or aryl groups at R4
exhibited weak binding to the B2 receptor (entries 1–4).
Para substitution of the benzoylterminus appeared to
be optimalfor binding affinity (entries 12–14). Com-
pounds with lipophilic substituents on the phenyl ring
(entries 5 and 6) showed only moderate activity whereas
more polar substituents such as methoxy, sulfone, sul-
fonamide, acetamide or nitrile were quite potent (entries
8–10, 14, and 16, respectively)
(6-Cl)3-Pyridyl
(6-CN)3-Pyridyl 74
(6-CN)3-Pyridyl103
(4-CN)Ph
(4-CN)Ph
(4-CN)Ph
(4-CN)Ph
(4-CN)Ph
271
Me
Me
n-Pr
Allyl
5500
55
Me
Me
3890
514
ClMe
ClMe
ClMe
ClMe
ClMe
Et
H
10
n-Pr
n-Bu
i-Amyl(4-CN)Ph
(4-CN)Ph
(4-CN)Ph
(4-CN)Ph
27
29
44
38
Heterocyclic substitution for phenyl was well tolerated.
Indeed, replacement of the phenyl (entry 3) with thienyl
(entry 15) gave a compound with a 10-fold increase in
binding affinity. In addition, one of the most potent
analogues contained a nitrile-substituted pyridyl group.
This result was not surprising given that one of the most
potent phenyl analogues also contained a nitrile sub-
stituent. Other pyrrole regioisomers were explored but
the 2,4 and the 3,5 isomers exhibited weaker activity
than the 2,5 isomers. In addition, removalof the car-
bonylgroup between the pyrroel and the phenylring
abolished activity (data not shown).
Table 2. Binding affinities of pyrrolyl propionamides at the B2
receptor
Entry
R1
R4
Ki (nM)
31
32
33
34
35
36
37
38
Me
Me
Me
Me
2-Thienyl141
3-Pyridyl304
(6-Cl)3-Pyridyl
(4-CN)Ph
We also synthesized a select number of congeners in
which the chain length was increased. Using the SAR
extracted from the pyrrolyl acetamide series, we were
able to obtain propionamide homologues with excellent
affinity for the B2 receptor (Table 2). These homologues
were also shown to be functional antagonists at the B2
receptor.
126
19
Cl2-Thienyl 304
Cl3-Pyridyl 15
)3-PyrCidly(6l-Cl38
Cl(4-CN)Ph
4
a steric requirement previously suggested by Fujisawa.16
Secondly, compounds derived from either the dichlori-
nated or dimethylated anilines were essentially equi-
potent (entries 16–17, 18–19, and 20–21).
Potent compounds were further evaluated in an in vivo
modelof antinociception ( Table 3).17 Although com-
pounds containing a benzoyl terminus generally exhib-
ited better binding affinities, pyridyl-containing
analogues demonstrated more consistent oral activity in
vivo. For example, cyano-substituted phenyl propion-
amide (38) had superior binding affinity at the B2
However, there were exquisite and unique SAR features
attributed to the incorporation of pyrrolyl scaffolds. In

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M. A. Youngman et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1341–1344
receptor but showed weak in vivo activity upon oral
dosing (23% inhibition at 160 mmol/kg). By contrast,
chloro-substituted pyridyl analogue (37) was more
active upon oraldosing perhaps due to better aqueous
solubility. Furthermore, several analogues exhibited
good oralpotency in this modelwith the most potent
analogue (37) having an ED50 value of 23 mmol/kg.
Oku, T.; Tanaka, H. J. Med. Chem. 1998, 41, 564. (b) Abe, Y.;
Kayakiri, H.; Satoh, S.; Inoue, T.; Sawada, Y.; Inamura, N.;
Asano, M.; Hatori, C.; Sawai, H.; Oku, T.; Tanaka, H. J.
Med. Chem. 1998, 41, 4053.
7. Hoyer, D.; Awad, M. M. A.; Salvino, J. M.; Seoane, P. R.;
Dolle, R. E.; Houck, W. T.; Sawurtz, D. G. Bioorg. Med.
Chem. Lett. 1995, 5, 367.
8. (a) Dziadulewicz, E. K.; Ritchie, T. J.; Hallett, A.; Snell,
C. R.; Ko, S. Y.; Wrigglesworth, R.; Hughes, G. A.; Dunstan,
A. R.; Bloomfield, G. C.; Drake, G. S.; Brown, M. C.; Lee,
W.; Burgess, G. M.; Davis, C.; Yaqoob, M.; Perkins, M. N.;
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2000, 43, 769. (b) Amblard, M.; Daffix, I.; Bedos, P.; Berge,
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In conclusion, we have designed and synthesized a novel
series of alkylpyrrolyl amides with selective, nanomolar
binding affinity to the bradykinin B2 receptor. These
compounds have also been shown to have oral activity
in an in vivo modelof antinociception. These resutls
suggest that this novelseries of compounds may be
usefulfor the treatment of various pain and inflamma-
tory states, and asthma.
9. Kayakiri, H.; Abe, Y.; Oku, T. Drugs Future 1999, 24, 629.
10. Carson, J. R. US Patent 3,998,844, 1976. Chem. Abst.
1977, 584363.
References and Notes
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14. Zhang, S. P.; Codd, E. Life Sci. 1998, 62, 2303 This series
of compounds exhibited no significant binding to the B1
receptor (data not shown).
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over the 15-min period immediately following injection of
kaolin. The mean number of counts (ꢂSEM) for a group of
animals receiving test compound (T) orally, 30 min prior to
kaolin, was compared to the mean for animals dosed similarly
with vehicle (V, 0.05N HCl). Percent inhibition was calculated
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