3-Aryl pyridone derivatives. Potent and selective kappa opioid receptor agonists

Article abstract of DOI:10.1016/S0960-894X(01)00691-6

A new series of 3-aryl pyridone based kappa opioid receptor agonists was designed and synthesised, based on an understanding of the classical kappa opioid receptor pharmacophore. The most potent of the new compounds were comparable to U-69,593 in receptor affinity, selectivity and functional agonist effect at the cloned human kappa opioid receptor.

Full text of DOI:10.1016/S0960-894X(01)00691-6

Bioorganic & Medicinal Chemistry Letters 12 (2002) 197–200
3-Aryl Pyridone Derivatives. Potent and Selective Kappa Opioid
Receptor Agonists
Graeme Semple,a,* Britt-Marie Andersson,b Vijay Chhajlani,b Jennie Georgsson,a
Magnus Johansson,a Marcel Lindschoten,a Fritof Ponten,a Asa Rosenquist,a
Henrik Sorensen,a Lars Swansona and Marianne Swansona
aDepartment of Medicinal Chemistry, AstraZeneca R&D Molndal, S-431 83, Molndal, Sweden
¨
¨
bDepartment of Biochemistry and Cell Biology, AstraZeneca R&D Molndal, S-431 83, Molndal, Sweden
¨
¨
Received 29 August 2001; revised 18 October 2001; accepted 19 October 2001
Abstract—A new series of 3-aryl pyridone based kappa opioid receptor agonists was designed and synthesised, based on an
understanding of the classical kappa opioid receptor pharmacophore. The most potent of the new compounds were comparable to
U-69,593 in receptor affinity, selectivity and functional agonist effect at the cloned human kappa opioid receptor. # 2002 Elsevier
Science Ltd. All rights reserved.
Non-peptide ligands of the kappa opioid receptor
(KOR) have been known for many years. The first
selective agonist compounds were described by Upjohn
in the 1980s1 (e.g., 1, Fig. 1) and were rapidly followed
by related structures, in particular from ICI (2)2 and
later Glaxo (3), SmithKlineBeecham (4) and others.3 All
of these compounds were initially targeted towards var-
ious pain indications but preliminary clinical studies
showed that they produced severe centrally-mediated
side effects, such as diuresis, sedation and dysphoria,4
and as a result were all dropped from development.
Despite the implication from several sources that KOR
agonists may still be useful in mediating various per-
ipherally mediated pain states, attempts to restrict
access of KOR agonists to the CNS have thus far been
only partly successful5 and no selective KOR agonist
compound has yet reached the market.
agonist activity. Our analysis of these clearly implied
that the global active conformation was of an extended
nature. We next applied simple conformational model-
ling techniques to explore the core structure of the open
series (2, the most flexible example) to try and find new,
restrained molecules which would mimic the active
conformation. Amongst the classical KOR agonist ser-
ies, the substituted phenyl acetic group and mimetics
thereof, are an important determinant for receptor affi-
nity. Perhaps as a result, this region has been much less
well explored as a site of conformational restriction and
so we began by modelling a number of cyclic bridged
structures involving the N-methyl group and the phenyl
acetyl carbon (Fig. 2). Delving further into the literature,
We have been interested in the design of new KOR
agonist scaffolds, which could eventually be modified to
act selectively in the periphery as a potential treatment
for visceral pain. A simple comparison across structural
series of known KOR agonists led us to the obvious
conclusion that several different conformational restric-
tions when applied to the classical N–C–C–N–CO
pharmacophore, retain good KOR binding affinity and
*Corresponding author. Tel.:+46-31-776-2184;fax:+46-31-776-3710;
e-mail: graeme.semple@astrazeneca.com
Figure 1. Known kappa agonists.
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00691-6

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G. Semple et al. / Bioorg. Med. Chem. Lett. 12 (2002) 197–200
Scheme 1. Reagents and conditions: (i) H2O2, AcOH, 80 ꢀC, 18 h, 90%; (ii) Ac2O, 80 ꢀC, 43%; (iii) (a) NaH, DMF, 0 ꢀC, 1 h; (b) 1-(2-chloro-2-
phenylethyl) pyrrolidine, rt 60% (two steps).
Scheme 2. Reagents and conditions: (i) Br2, 1MKBr, rt 22%; (ii) (a) NaH, DMF, 0 ꢀC, 1 h; (b) 1-(2-chloro-2-phenylethyl) pyrrolidine, rt
60%; (iii) ArB(OH)2, PdOAc, dioxan, NaHCO3, 80 ꢀC, 4 h, 40–90%; (iv) NBS, AcOH, rt 4 h, 55%.
we found that cyclic urea compounds with sub-nano-
molar affinity for the kappa receptor6 and saturated
lactam analogues related to earlier series7 have both
been described (Fig. 2). We were encouraged by the
reported activity of these types of compounds, and as
the conformation of these five-membered rings was very
flat in our models, we decided to investigate the pyri-
done 5, which we surmised would be a close mimic of
these known active series.
3-phenyl pyridine 9a by oxidation to the N-oxide and
acid catalysed rearrangement as previously described.8
The analogous pyridone (11b, R=4-CF3) was prepared
in a similar manner from the appropriate substituted
aryl pyridine prepared in turn from the Grignard medi-
ated coupling of 3-bromopyridine and 4-(tri-
fluoromethyl)-bromobenzene.9
These pyridones were readily alkylated by treatment
with sodium hydride at 0 ꢀC followed by 1-(2-chloro-2-
phenylethyl) pyrrolidine,10 prepared via the corre-
sponding alcohol,11 [CAUTION, the free base of 1-(2-
chloro-2-phenylethyl) pyrrolidine is a potent mustard
agent] providing the initial target compounds 5a and 5b.
We initially synthesised compounds of this type by the
route shown in Scheme 1. Pyridone 11a (R=H) was
synthesised in two steps from commercially available
The prototypical compound (5a) showed an IC50 of
56 nM for binding to the cloned human kappa opioid
receptor,12 and had no affinity for the related delta and
mu opioid receptors. In addition, 5a showed a clear full
agonist effect (>95% Emax relative to U-69,593) in our
in vitro functional test.13 Substitution of the terminal
phenyl ring with 4-CF3, (5b), provided significantly
improved kappa receptor binding (Table 1) and func-
tional effects [ED50=49.4Æ5.6 nM (Emax>95%) c.f.
23.8Æ1.76 nM for U-69,593] over the parent com-
pound. As the corresponding substitution also provides
an improvement in activity in the classical open series,14
we were interested in expanding the available range of
compounds in order to see how closely our new com-
pounds would mimic the SAR of the classical agonist
series. For this investigation we examined only the
binding affinities of the new compounds for opioid
receptors, having demonstrated in principle that the new
series had functional agonist properties. In addition, we
utilised an alternative synthetic route, making use of a
palladium catalysed arylation as the final step to give
more flexibility in the number and range of aryl groups
that we could incorporate. This route is outlined in
Scheme 2.
Figure 2. Design of pyridone-based kappa agonists.

G. Semple et al. / Bioorg. Med. Chem. Lett. 12 (2002) 197–200
Table 1. Ligand binding data for kappa, delta and mu opioid receptors
199
Compd
Ar
k-binding IC50 (nM)
d-binding IC50 (nM)
m-Binding IC50 (nM)
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
5s
5t
17c
17m
U-69,593
Ph
4-CF3–Ph
4-Cl–Ph
4-OMe–Ph
4-F–Ph
4-OCF3–Ph
2-OMe–Ph
2-CF3–Ph
3-NO2–Ph
3-Cl–Ph
56.3 (32.1–80.4)
8.7 (3.3–14.1)
5.5 (2.65–8.71)
49.4 (22.6–76.2)b
34.8 (19.4–45.2)
34.2 (27.5–43.8)
19.5 (4.97–38.3)
5.7 (2.64–7.9)
2.2 (1.72–2.67)b
2.4 (1.74–2.89)
5.3 (3.71–7.92)
79.3 (52.9–92.9)
2.3 (2.1–2.5)b
3.4 (2.19–4.71)b
1.5 (0.66–2.26)
3.44 (1.73–5.3)
22.5 (16.6–26.3)
271a
>10,000
>10,000
>10,000
5214a
>10,000
2716
4840 (677–9000)
1464a
>10,000
1100 (145–1790)
1200 (237–2170)
1680 (871–3250)
3910 (1820–5510)
308 (229–388)
4280 (2500–6540)
>10,000
>10,000a
>10,000
>10,000a
>10,000
>10,000
>10,000
>10,000
639 (120–1340)
>10,000
4350 (1250–7450)
4170 (1220–5980)
>10,000
>10,000
n.d.
3-CN–Ph
3-Me–Ph
3,4-Cl2–Ph
2-OMe, 5-F–Ph
2-OMe, 5-Cl–Ph
2,5-(OMe)2–Ph
2,5-F2–Ph
2-Benzofuran
2-Thiophene
2-Naphthalene
4-Cl–Ph
2064a
3460 (1490–5050)
1240 (318–2370)
>5000
>10,000
n.d.
n.d.
1177a
n.d.
31.9 (17.7–56.4)
524a
>10,000
n.d.
n.d.
5844Æ1420
2680 (1630–4680)
n.d.
n.d.
3,4-Cl2–Ph
—
1494a
2.0Æ0.1
248Æ23.8
a
Values for kappa binding are the arithmetical mean of at least three determinations (except n=1 and bn=2) and are shown with 95% confidence
limits (except for U-69,593 which isÆSEM). Values for delta and mu binding are the mean of at least two determinations (except a n=1).
n.d.=not determined.
3-Bromopyridone (13) was prepared by treatment of
2-hydroxypyridine (12) with bromine in KBr solution.15
Alkylation with 1-(2-chloro-2-phenylethyl) pyrrolidine
using the method outlined above, provided the key
intermediate 14 in good yield. The Suzuki coupling
reaction16 was accomplished on a 10–15 mg scale (of
substrate 14) with a wide range of boronic acid deriva-
tives. In a typical procedure, an excess of the boronic
acid was reacted with 14 in the presence of 3 mol% of
Pd(OAc)2 and sodium bicarbonate at 80 ꢀC in dioxan
for 4 h, in a 96-well Robbins reaction block. The result-
ant products were isolated in good yield and >85%
purity (as determined by HPLC–MS) following parallel
ion exchange purification on pre-packed SCX columns.
assist in providing good affinity and selectivity for the
KOR in combination with additional substituents in the
5-position. The most potent compound tested was 5o,
with an affinity for the KOR comparable to that of the
literature standard compound, U-69,593 in our hands.
Incorporation of either thiophene or fused aromatic
rings lead to a significant decrease in affinity over the
most potent substituted phenyl analogues. These data
suggested to us that our pyridone analogues had a
similar SAR to the classical open series2 with regard to
substitutions on the terminal aromatic ring inferring a
similar mode of binding.
Finally, we also prepared the isomeric 5-aryl pyridone
analogues 17, in which the presumed pharmacophore is
disrupted by arranging the carbonyl and aryl groups in
a different relative orientation. An alternative bromina-
tion of 2-hydroxypyridine using NBS,17 to provide 15
(Scheme 2), followed by alkylation and Suzuki arylation
as described above, provided target compounds 17 in
good yield.
After screening in the KOR binding assay at a single
concentration of either 1 or 10 mM, selected examples were
further purified to homogeneity (>96% purity) by parallel
preparative HPLC. Full dose–response curves were then
determined for binding to kappa, delta and mu opioid
receptors and the data provided in Table 1 represents
mean IC50 values for the fully purified material.
The significantly poorer binding affinity of these ana-
logues for the KOR (Table 1) is, we believe, due to the
loss of a hydrogen bond interaction between the pyri-
done carbonyl and the receptor and we feel that, taken
together, all the data validate our original hypothesis,
that the above described 3-aryl pyridones bind to the
KOR in a similar way to the classical open series.
Substitution at the 4-position of the aryl ring with either
trifluoromethyl- (5b) or chloro- (5c) groups provided an
improvement in binding affinity for the KOR compared
with the unsubstituted compound 5a. Other 4-sub-
stituents had little effect. Substitution at the 3-position
was also fruitful, with the 3-nitro (5i), 3-chloro (5j) and
3-cyano (5k) derivatives all having better KOR affinity
than 5a. The 3-chloro derivative however also showed
significant binding to the mu opioid receptor. Incor-
porating two substituents onto this ring appeared to be
beneficial. In particular, the 2-methoxy substituent,
whilst having little effect on its own (5g), was able to
In summary, we have designed and synthesised a new
series of kappa opioid receptor ligands based on an
understanding of the classical KOR pharmacophore.
The new series provides a novel template with several
potential points of attachment for functional groups,

200
G. Semple et al. / Bioorg. Med. Chem. Lett. 12 (2002) 197–200
for example, to one of the three aromatic rings, which
may be used to restrict access to the CNS either by
increasing polar surface area and/or decreasing logD.
Their close similarity to the classical KOR agonists
suggests we can exploit existing literature knowledge
regarding the incorporation of such groups into our new
series and such studies with compounds of this type will
be reported in due course.
8. Moran, D. B.; Morton, G. O.; Allbright, J. D. J. Hetero-
cycl. Chem. 1986, 23, 1071.
9. Wickstrom, H.; Andersson, B.; Elebring, T.; Svensson, K.;
Carlsson, A.; Largent, B. J. Med. Chem. 1987, 30, 2169.
10. Hacksell, U.; Arvidsson, L. E.; Svensson, U.; Nilsson,
J. L.; Sanchez, D.; Wikstrom, H.; Lindberg, P.; Hjorth, S.;
Carlsson, A. J. Med. Chem. 1981, 24, 1475.
11. Shapiro, S. L.; Soloway, H.; Freedman, L. J. Am. Chem.
Soc. 1958, 80, 6060.
12. All opioid receptor binding affinites were determined by
classical filter binding methods, measuring the displacement of
the appropriate radiolabelled ligand from membranes of
HEK293 cells overexpresing the requisite human opioid
receptor. Ligands used were [125I]-(d-Pro10)-Dynorphin A(1-
11) (k), [125I]-Enkephalin (m) and [125I]-Deltorphin (d).
13. Functional activity was determined using a radiolabelled
[35S]-GTPgS assay, again using membranes of HEK-293 cells
overexpresing the human kappa opioid receptor.
14. The classical ICI series was recently re-investigated, and
the CF3 group also shown to provide an improved peripheral
restriction. Kumar, V.; Marella, M. A.; Cortes-Burgos, L.;
Chang, A.-C.; Cassel, J. A.; Daubert, J. D.; DeHaven, R. N.;
DeHaven-Hudkins, D. L.; Gottshall, S. L.; Mansson, E.;
Maycock, A. L. Bioorg. Med. Chem Lett., 2000, 10, 2567.
15. Tee, O. S.; Paventi, M. J. Am. Chem. Soc. 1982, 104, 4142.
16. Suzuki coupling of aryl boronic acids to pyridone triflates
has been described using an alternative catalytic system. Col-
lins, I.; Castro, J. L. Tetrahedron Lett. 1995, 40, 4069.
17. Fox, B. A.; Threlfall, T. L. Organic Syntheses; Wiley: New
York, 1973; Collect Vol. V, p 346.
References and Notes
1. Szmuszkovicz, J.; Von Voigtlander, P. F. J. Med. Chem.
1982, 25, 1125.
2. Costello, G. F.; James, R.; Shaw, J. S.; Slater, A. M.;
Stutchbury, N. C. J. J. Med. Chem. 1991, 34, 181.
3. Jones, R. M.; Paterlini, M. G. Curr. Opin. Drug Discov.
Develop. 1999, 1, 175.
4. Rimoy, G. H.; Wright, D. M.; Bhaskar, N. K.; Rubin, P. C.
Eur. J. Clin. Pharmacol. 1994, 46, 203.
5. Giardina, G.; Clarke, G. D.; Grugni, M.; Sbacchi, M.;
Vecchietti, V. Farmaco 1995, 50, 405.
6. Yamanouchi Pharmaceutical Co. PCT patent application
WO93/03011.
7. Clemence, F; Fortin, M; Le Martret, O. European Patent
application, EP0437120; Cheng, C. Y.; Lu, H. Y.; Lee, F.-M;
Tam, S. W. J. Pharm. Sci. 1990, 79, 758.