2-Phenyl-4-quinolinecarboxamides: A novel class of potent and selective non-peptide competitive antagonists for the human neurokinin-3 receptor

Full text of DOI:10.1021/jm9602423

© Copyright 1996 by the American Chemical Society
Volume 39, Number 12
J une 7, 1996
Communications to the Editor
potential therapeutic indications for NK-1 and NK-2
2-P h en yl-4-qu in olin eca r boxa m id es: A
Novel Cla ss of P oten t a n d Selective
Non -P ep tid e Com p etitive An ta gon ists for
th e Hu m a n Neu r ok in in -3 Recep tor
receptor antagonists.10-13 In contrast to the NK-1 and
NK-2 receptor research area, there is limited informa-
tion on the biology and potential pathophysiological
significance of the NK-3 receptor. This was, to a large
extent, due to the lack of sufficient potency and selectiv-
ity of the peptide NK-3 antagonists described thus far14
and to the absence of non-peptide NK-3 receptor ligands
until recently. However, the recent disclosure of the
“peptoid” NK-3 antagonist PD 15767215 and the peptide-
derived PD 16118216 has provided improved reagents
for these studies and stimulated the search for more
potent and metabolically stable non-peptide NK-3 re-
ceptor antagonists.
Giuseppe A. M. Giardina,*,† Henry M. Sarau,‡
Carlo Farina,† Andrew D. Medhurst,§ Mario Grugni,†
J ames J . Foley,‡ Luca F. Raveglia,†
Dulcie B. Schmidt,‡ Roberto Rigolio,† Marco Vassallo,†
Vittorio Vecchietti,† and Douglas W. P. Hay‡
Department of Chemistry, SmithKline Beecham S.p.A.,
Via Zambeletti, 20021 Baranzate, Milano, Italy,
Department of Pulmonary Pharmacology,
SmithKline Beecham Pharmaceuticals, 709 Swedeland
Road, King of Prussia, Pennsylvania 19406-0939, and
Department of Neurology Research, SmithKline Beecham
Pharmaceuticals, New Frontiers Science Park,
The human NK-3 (hNK-3) receptor mRNA has been
detected, using polymerase chain reaction (PCR), to
various regions in the central nervous system (CNS) and
also, albeit to a lesser extent, in some peripheral tissues,
including kidney, placenta, lung, and colon.17 Activation
of NK-3 receptors modulates the release of various
transmitters in the CNS and periphery,18-20 suggesting
that they may have a neuromodulatory role.
Recently, (S)-(+)-N-{{3-[1-benzoyl-3-(3,4-dichlorophen-
yl)piperidin-3-yl]prop-1-yl}-4-phenylpiperidin-4-yl}-N-
methylacetamide, SR 142801 (1, Chart 1), was reported
as the first potent non-peptide NK-3 receptor antago-
nist.21,22 Chemically, SR 142801 derives from a con-
strained analog of SR 48968, a potent NK-2 receptor
antagonist (Ki ) 0.51 nM, for displacement of [125I]-
NKA) in rat duodenum membranes,7 which has moder-
ate affinity for NK-3 receptors (IC50 ) 320 nM, for
displacement of [3H]senktide {succinyl-[Asp9MePhe8]-
SP(6-13)}) in guinea pig cerebral cortex membranes.23
We now report on the discovery of a novel class of
potent and selective non-peptide NK-3 receptor antag-
onistssstructurally unrelated to the piperidine deriva-
tives SR 142801 and SR 48968swhich are based on the
2-phenylquinoline backbone.24 Chemical synthesis
(Scheme 1), radioligand binding affinities for the cloned
human neurokinin receptors stably expressed in CHO
cell lines (hNKs-CHO),17,25,26 in vitro functional activity
in the rabbit isolated iris sphincter muscle preparation
(antagonism of senktide-induced contraction),27 and
structure-activity relationships (SARs) of the novel
Third Avenue, Harlow, Essex, England CM19 5AW
Received March 27, 1996
Pharmacological and molecular biological studies
indicate the existence of at least three human tachyki-
nin receptor subtypes, designated neurokinin-1 (NK-1),
neurokinin-2 (NK-2), and neurokinin-3 (NK-3),1-3 which
belong to the superfamily of G-protein-coupled receptors
possessing seven transmembrane domains.4 The en-
dogenous ligands for these receptors constitute a family
of small neuropeptides, named tachykinins or neuroki-
nins, which share the common carboxy-terminal region
Phe-X-Gly-Leu-MetNH2. The main mammalian tachy-
kinins, substance P, neurokinin A (NKA), and neuro-
kinin B (NKB), interact with all three tachykinin
receptors, although there is a defined agonist rank order
of potency for NK-1, NK-2, and NK-3 receptors, respec-
tively; for example, for the NK-3 receptor the rank
potency order is NKB > NKA > substance P.
Over the past few years potent and selective peptide
and non-peptide antagonists for the NK-1 and NK-2
receptors have been identified.5-8 These pharmacologi-
cal tools accelerated the clarification of physiological and
pathophysiological roles of these receptors9 and the
† Italy.
‡ USA.
§ England.
S0022-2623(96)00242-7 CCC: $12.00 © 1996 American Chemical Society

2282 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 12
Communications to the Editor
Sch em e 1.a Synthesis of Compounds of General
Ch a r t 1
Formula 6a -c and 7a -c
potent NK-3 receptor antagonists 6a -c and 7a -c
(Table 1) will be summarized; a comparison to SR
142801 will be presented. For compound 7c, functional
activity in HEK 293 cells expressing the hNK-3 receptor
(NKB-induced Ca2+ mobilization)22 will be described.
Resu lts a n d Discu ssion . The 4-quinolinecarboxa-
mide derivative 2, specifically designed to arrange the
phenyl ring in position 2 and the benzene ring of the
carboxamide side chain in a relative space position
suitable for a potential interaction with NK (particularly
NK-1) receptors,28 was shown to possess no affinity for
hNK-1 receptors (Ki > 10 µM, for displacement of [3H]-
substance P binding from hNK-1-CHO membranes) and
moderate affinity for the hNK-3 receptor (Ki ) 533 nM,
for displacement of [125I]MePhe7-NKB binding from
hNK-3-CHO membranes). Thus, compound 2 was uti-
lized as a structural lead, suitable for chemical modi-
fications aimed at optimizing the NK-3 receptor binding
affinity of the compound, by variation of the carboxa-
mide side chain in position 4 and of the substitution
pattern on the quinoline ring system.
The synthesis of compounds 6a -c and 7a -c was
accomplished as described in Scheme 1. Isatin 3 was
submitted to the Pfitzinger reaction, by refluxing with
phenyl ketones 4a -c in the presence of an excess of
potassium hydroxide to obtain the 2-phenylquinoline-
4-carboxylic acids 5a ,b in high yields; 3-hydroxy-2-
phenylquinoline-4-carboxylic acid (5c) was obtained by
refluxing the corresponding methoxy intermediate in
48% hydrobromic acid. Secondary carboxamides 6a -c
and 7a -c were obtained by coupling the carboxylic acids
5a -c with the appropriate primary amines in a 7:3
mixture of THF and MeCN in the presence of dicyclo-
hexylcarbodiimide (DCC) and 1-hydroxybenzotriazole
(HOBT) to maximize yields and avoid racemization of
the resulting compounds.
a
Reagents: (a) KOH, EtOH, reflux; (b) R1 ) OMe, 48% HBr,
reflux; (c) methyl phenylglycinate hydrochloride, DCC, HOBT,
Et3N, THF/MeCN, room temperature; (d) (S)-1-phenylpropyl-
amine, DCC, HOBT, THF/MeCN, room temperature.
senktide-induced contractions) are enantioselective prop-
erties of this chemical series, the (R)-stereoisomer 6b
(hNK-3-CHO binding, Ki ) 13.3 nM) being about 2-fold
more potent than racemic 6a and almost 2 orders of
magnitude more potent than the (S)-enantiomer 6c
(hNK-3-CHO binding, Ki ) 925 nM) as shown in Table
1. Neurokinin receptor selectivity studies using radio-
ligand competition binding with hNK-2 and hNK-1
receptors expressed in CHO cell membranes demon-
strated that compound 6b has an exquisite selectivity
for hNK-3 with respect to the hNK-1 receptor (hNK-1/
hNK-3 Ki ratio >7500) and a good selectivity versus the
hNK-2 receptor (hNK-2/hNK-3 Ki ratio ) 91).
Further chemical efforts were aimed at (a) replacing
the ester functionality to circumvent potential metabolic
instability problems and (b) optimizing the NK-3 recep-
tor binding affinity and selectivity. Incorporation of a
variety of substituents at the benzyl position (including
alkyl, aralkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxy-
alkyl, acyl, acid, and amide groups) revealed that linear
two or three carbon atom chains maintained high and
enantioselective NK-3 binding affinity and in vitro
functional antagonist activity (data not shown). The
ethyl derivative 7a (hNK-3-CHO binding, Ki ) 18.0 nM)
was therefore selected to investigate the effect of the
quinoline substitution pattern on biological activities.
Whereas substitution at position 5, 6, 7, and 8 of the
quinoline ring system produced compounds with poten-
cies lower or similar to that of the unsubstituted analog,
incorporation of alkyl groups at position 3 of the
quinoline ring resulted, in general, in an increased
binding affinity for the hNK-3 receptor. For example,
incorporation of a methyl group, as in compound 7b (R
Incorporation of the methoxycarbonyl substituent at
the benzyl position of compound 2 and removal of the
7-methoxy group produced a 17-fold increase in hNK-3
receptor binding affinity (Table 1, cf. 6a , hNK-3-CHO
binding, Ki ) 30.7 nM, with compound 2, hNK-3-CHO
binding, Ki ) 533 nM). Further studies with enantio-
merically pure stereoisomers 6b and 6c revealed that
hNK-3 receptor binding affinity and functional activity
in rabbit isolated iris sphincter muscle (antagonism of

Communications to the Editor
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 12 2283
Ta ble 1. Chemical Structures, Binding Affinities at Cloned Human Neurokinin Receptors (hNK-1, hNK-2, and hNK-3) Expressed in
CHO Cells, and in Vitro Functional Activities (Antagonism of Senktide-Induced Contractions) in Rabbit Isolated Iris Sphincter
Muscle (RISM) Preparation for Compounds 6a -c, 7a -c, and SR 142801
antagonism of
senktide-induced
binding affinities, Ki mean ( SEM (nM)a
config
(*)
contractions in RISM,b
compound
R
R1
hNK-3c
hNK-2d
hNK-1e
Kbf mean ( SEM (nM)a
6a
6b
6c
7a
7b
7c
COOMe
COOMe
COOMe
Et
Et
Et
H
H
H
H
Me
OH
(R,S)
(R)
(S)
(S)
(S)
30.7 ( 3.8
13.3 ( 2.7
925 ( 250
18.0 ( 1.0
4.2 ( 0.6
1.0 ( 0.1
1.2 ( 0.2
2947 ( 585
1221 ( 189
8333 ( 926
237 (2)
>100000
>100000
>100000
>100000
>100000
>100000
42 ( 12
43 ( 6.2
3982 (2)
9.7 ( 1.7
7.7 ( 1.0
5.4 ( 3.4
2.0 ( 0.5
277 ( 57
(S)
144 ( 22
SR 142801 (1)g
40.3 ( 5.5
1300 (2)
a
b
Average of three to eight independent determinations (n ) 3-8), unless otherwise indicated in parentheses. According to ref 27.
c Inhibition of [125I]MePhe7-NKB binding in hNK-3-CHO cell membranes, according to ref 17. Inhibition of [125I]NKA binding in hNK-
d
2-CHO cell membranes, according to ref 25. e Inhibition of [3H]substance P binding in hNK-1-CHO cell membranes, according to ref 26.
f The equilibrium-dissociation constant Kb for the antagonist-NK-3 receptor complex was calculated from the equation: Kb ) [B]/CR -
g
1 where CR is the concentration ratio of agonist used in the presence and absence of antagonist B. In-house data.
) Et, R1 ) Me), produced a 4-fold increase of the hNK-3
receptor binding affinity (hNK-3-CHO, Ki ) 4.2 nM),
possibly due to a limitation of the conformational space
of the 4-carboxamide side chain.
a slope of the regression line of 1.2, consistent with
competitive antagonism. Unlike SR 142801,29 com-
pound 7c displayed no time dependence for activity and
its effects were rapidly reversed by washing, providing
further evidence that it is acting as a reversible,
competitive antagonist.
This finding led to a comprehensive investigation of
the optimal substituent at position 3, aimed at improv-
ing NK-3 binding affinity, in vitro functional antagonist
activity, and selectivity for the hNK-3 versus hNK-2
receptors (a feature apparently reduced in the R-Et
series, cf. compound 7a with 6b). (S)-(-)-N-(R-Ethyl-
benzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide (7c,
SB 223412), featuring a hydroxy group at position 3 of
the quinoline nucleus, possessed the best overall profile
identified among compounds synthesized in this class
thus far. Compound 7c is, in fact, as potent (hNK-3-
CHO binding, Ki ) 1.0 nM; antagonism of senktide-
induced contraction in rabbit isolated iris sphincter
muscle, Kb ) 5.4 nM) as the reference compound SR
142801 (hNK-3-CHO binding, Ki ) 1.2 nM; antagonism
of senktide-induced contraction in rabbit isolated iris
sphincter muscle, Kb ) 2.0 nM), but is more selective
for hNK-3 versus the other tachykinin receptors: it has
a hNK-2/hNK-3 Ki ratio of 144 (vs 13 determined for
the 3-H parent, 7a , and 34 determined for SR 142801)
and a hNK-1/hNK-3 Ki ratio > 100 000 (vs 1000 for SR
142801).
Moreover, compound 7c (at concentrations of 1 or 10
µM) was without effect in a multitude of assays for
various receptors, ion channels, and enzymes (data not
shown), including sodium channel (site 2) and opioid (µ,
κ, δ) receptors for which SR 142801 was described to
possess binding affinities in the 0.1 to 1 µM concentra-
tion range.21
The cellular functional activity of compound 7c was
also evaluated utilizing HEK 293 cells expressing the
hNK-3 receptor; compound 7c, at 10-1000 nM concen-
tration range, produced a concentration dependent
antagonism of NKB-induced Ca2+ mobilization with a
Kb of 3.0 nM. Schild plot analysis of these data revealed
In summary, through the use of cloned human neu-
rokinin receptor assays, we have discovered a novel
chemical class of potent and selective non-peptide
competitive antagonists for the hNK-3 receptor based
on the quinoline structure; the most prominent member
is compound 7c, which has equivalent potency and
greater selectivity for the hNK-3 versus the hNK-2 and
hNK-1 receptors than SR 142801 (1), the only potent
non-peptide NK-3 receptor antagonist described to date.
We have also shown that these novel NK-3 receptor
antagonists have potent functional activity in the rabbit
isolated iris sphincter muscle preparation. Compounds
7b and 7c should prove to be extremely useful phar-
macological tools for anatomical localization and in vitro
and in vivo functional characterization of hNK-3 recep-
tors. Information gained from such studies will help
to elucidate the most appropriate therapeutic indica-
tions for selective NK-3 receptor antagonists.
A more detailed description of our investigations
within this chemical class, including SARs for the ester
and the 2-phenyl ring replacements, and for the quino-
line ring substitution will be reported in subsequent
manuscripts, along with the results of our studies aimed
at the replacement of the quinoline ring by other
(hetero)aromatic systems.
Ack n ow led gm en t. We are grateful to J oseph Wein-
stock, Fabrizio Bellucci, Geoffrey D. Clarke, and Paola
Zaratin for the helpful discussions; we acknowledge
Davide Graziani and Stefano Cavagnera for their chemi-
cal technical expertise and Karl Erhard for the produc-
tion of SR 142801 via chiral HPLC separation of the
racemic mixture (in-house produced); and we also thank

2284 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 12
Communications to the Editor
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J M9602423