The design and synthesis of the high efficacy, non-peptide CCK1 receptor agonist PD 170292

Article abstract of DOI:10.1016/S0960-894X(00)00198-0

The design, synthesis and biological actions of a novel, non-peptide CCK₁ receptor agonist (PD 170292) which exhibits a similar pharmacological profile to the CCK analogue JMV 180 is reported. PD 170292 was designed based on a consideration of the structures of a peptide based CCK₁ receptor selective agonist and a peptoid CCK₂ receptor selective antagonist. (C) 2000 Elsevier Science Ltd. All rights reserved.

Full text of DOI:10.1016/S0960-894X(00)00198-0

Bioorganic & Medicinal Chemistry Letters 10 (2000) 1245±1248
The Design and Synthesis of the High Ecacy, Non-peptide
CCK1 Receptor Agonist PD 170292
N. Bernad, a B. G. M. Burgaud, b D. C. Horwell, b R. A. Lewthwaite, b J. Martinez a
and M. C. Pritchard b,*
aCCIPE-Faculte de Pharmacie, 15 Av. C. Flahault, 34060 Montpellier, Cedex, France
bParke-Davis Neuroscience Research Centre, Cambridge University Forvie Site, Robinson Way, Cambridge, CB2 2QB, UK
Received 14 February 2000; accepted 29 March 2000
AbstractÐThe design, synthesis and biological actions of a novel, non-peptide CCK1 receptor agonist (PD 170292) which exhibits a
similar pharmacological pro®le to the CCK analogue JMV180 is reported. PD 170292 was designed based on a consideration of the
structures of a peptide based CCK1 receptor selective agonist and a peptoid CCK2 receptor selective antagonist. # 2000 Elsevier
Science Ltd. All rights reserved.
Introduction
Chemistry
We have devoted considerable e€ort toward the devel-
opment of non-peptide ligands that act at receptors
which selectively bind, and are activated by, the neuro-
peptide cholecystokinin (CCK). This research e€ort has
led to the discovery of a variety of non-peptide ligands
which di€erentially bind both the CCK1 and CCK2
receptor types.1 One particular area of interest to us has
been the identi®cation of non-peptide agonists for the
CCK1 receptor type, a potential utility for which would
be in the treatment of obesity.2 Our approach to the
design of such non-peptide CCK1 agonists has principally
relied upon appending a key feature of the peptide CCK1
receptor selective agonist A-71623 (1) onto a ``peptoid''
motif which selectively binds the CCK2 receptor (2).3 This
methodology has led to the development of non-peptide,
full ecacy CCK1 receptor selective agonists although
with only mediocre potencies e.g. 3 (see Fig. 1).4
The starting point in the design of 3 was the phenethy-
lamide derivative 2. Although this peptoid ligand was one
of our preferred CCK receptor ligands at that point in the
research programme, it was a sub-optimal selection in that
it exhibited only mediocre anity for the CCK1 receptor
in addition to being selective for the CCK2 receptor type.6
Clearly the likelihood of developing a high anity/high
potency CCK1 receptor agonist would be increased by
selecting a starting template with greater anity for the
CCK1 receptor. To this end we selected compound 4 (PD
149164) as our starting point/template since, although
this compound was a CCK2 receptor selective antagonist,
it exhibited ꢀ10-fold improved CCK1 receptor anity
when compared to 2 in addition to being a full ecacy
CCK1 receptor agonist.7
Our strategy for improving CCK1 receptor recognition
essentially remained that of appending the aryl urea sub-
stituted Lys side chain in A-71623 (1) (thought to be key
for imparting CCK1 receptor anity/ecacy) onto an
appropriate point on the peptoid template. In contrast
to our original lead in this research area (3), the point of
attachment of the substituted Lys was to be the a-car-
bon of the C-terminal homologated Phe derivative in 4
(see Fig. 2). Thus, the substituted Lys group e€ectively
replaces the 4-¯uorophenyl group in 4 to give target
compound PD 170292 (6). PD 170292 (6) was deemed
to be structurally more closely related to A-71623 (1)
than was the case with 3 and, in addition, the compound
exhibited obvious structural similarities to a previously
In this paper we report on the design and synthesis of a
derivative of 3 with signi®cantly improved anity and
potency for the CCK1 receptor type. The target com-
pound PD 170292 (6) behaves as an agonist at the high-
anity and as an antagonist at the low-anity CCK1
binding sites. It has a pharmacological pro®le similar to
that of the CCK analogue JMV-180.5 We believe PD
170292 (6) to be the ®rst non-peptide derivative to pre-
sent such a pharmacological pro®le.
*Corresponding author. Tel.: +44-1223-210929; fax: +44-1223-
249106; e-mail: martyn.pritchard@wl.com
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00198-0

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N. Bernad et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1245±1248
Figure 1.
Figure 2.
published series of ``mixed'' CCK1/CCK2 receptor ago-
nists e.g., 5.8
low concentrations of CCK-8S (usually less than 100
pM) is closely related to amylase release while occupancy
of low anity sites by higher CCK-8S concentrations is
correlated to the inhibition of amylase secretion.9,10 PD
170292 (6) was able to stimulate amylase release from
isolated rat pancreatic acini with similar maximal e-
cacy as CCK-8S but without causing any decrease of
amylase release even at supramaximal concentrations.
The present results illustrate that PD 170292 (6) behaves
like the CCK-8 peptide analogue JMV-1805,11 being a
full agonist at the CCK1 high anity sites and an
antagonist at the CCK1 low anity sites.
Biology
The CCK receptor anities and functional activities of
the target compound 6 are reported in Table 1.
When isolated rat pancreatic acini are incubated with
increasing concentrations of CCK-8S, a typical biphasic
dose±response curve for amylase secretion is obtained
(Fig. 3), with a decrease in the response for supramax-
imal concentrations of CCK-8. It has been proposed
that the occupancy of high anity sites of receptors by
In addition to exhibiting high nanomolar anity for the
rat pancreatic CCK1 receptor, PD 170292 (6) was also

N. Bernad et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1245±1248
1247
Scheme 1. (i) 2-methylphenyl isocyanate, DMF, 60%; (ii) (a) EtO2CCl, TEA, THF, (b) ``CH2N2'' quant.; (iii) PhCO2Ag, TEA, TMSCH2CH2OH,
40%; (iv) HCO2H, quant.; (v) 2-Adoc(R)aMeTrp,6 HBTU, DIPEA, acid, DMF, 54%; (vi) TBAF, THF, 78%.
Table 1. CCK receptor anities13 and CCK1/CCK2 receptor functional activity12, 14 of a,a-disubstituted tryptophan derivatives
Compound
CCK Binding IC50 (nM)
CCK2
Amylase secretion
EC50 (nM)
Calcium mobilisation
EC50 (nM)
CCK1
CCK-8S
2
3
4 PD 149164
6 PD 170292
1.0
650
150
75
0.30
32
3600
0.083
6.7
0.02
NDa
480
(see ref 7)
5
2
ND
ND
ND
1.2
Antagonist IC50=40 nM
aND, means value not determined.

1248
N. Bernad et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1245±1248
Curr. Med. Chem. 1999, 6, 433. (b) Most recent publication on
CCK1 receptor agonists Bignon, E.; Bachy, A.; Boigegrain, R.;
Brodin, R.; Cottineau, M.; Gully, D.; Herbert, J.; Keane, P.;
Labie, C.; Molimard, J.; Olliero, D.; Oury-Donat, F.; Peter-
eau, C.; Prabonnaud, V.; Rockstroh, M.; Schae€er, P.; Ser-
vant, O.; Thurneyssen, O.; Soubrie, P.; Pascal, M.; Ma€rand,
J.; Le Fur, G. J. Pharmacol. Experimental Therapeutics 1999,
289, 742.
3. See Holladay, M. W.; Kopecka, H.; Miller, T. R.; Bednarz,
L.; Nikkel, A. L.; Bianchi, B. R.; Witte, D. G.; Shiosaki, K.;
Wel Lin, C.; Asin, K. E.; Nadzan, A. M. J. Med. Chem. 1994,
37, 630 and references cited therein.
4. (a) Bourne, G. T.; Horwell, D. C.; Pritchard, M. C. Bioorg.
Med. Chem. Lett. 1993, 3, 889. (b) Burgaud, B. G. M.; Hor-
well, D. C.; Pritchard, M. C.; Bernad, N.; Martinez, J.-M.
Tetrahedron: Asymmetry 1995, 6, 1081.
5. Galas, M. G.; Lignon, M. F.; Rodriguez, M.; Mendre, C.;
Fulcrand, P.; Laur, J.; Martinez, J. Am. J. Physiol. 1988, 254,
G176.
6. Horwell, D. C.; Hughes, J.; Hunter, J. C.; Pritchard, M. C.;
Richardson, R. S.; Roberts, E.; Woodru€, G. N. J. Med.
Chem. 1991, 34, 404.
Figure 3. E€ects of CCK-8S and PD 170292 (6) on amylase release
from rat pancreatic acini.
7. Hughes, J.; Dockray, G. J.; Hill, D.; Garcia, L.; Pritchard,
M. C.; Forster, E.; Toescu, E.; Woodru€, G. N.; Horwell, D.
C. Regul. Peptides 1996, 65, 15.
8. Dezube, M.; Sugg, E. E.; Birkemo, L. S.; Croom, D. K.;
Dougherty, R. W.; Ervin, G. N.; Grizzle, M. K.; James, M.
K.; Johnson, M. F.; Mosher, J. T.; Queen, K. L.; Rimele, T.
J.; Sauls, H. R.; Trianta®llou, J. A. J. Med. Chem. 1995, 38,
3884.
able to recognise CCK2 receptors in guinea pig brain
membranes with similar anity. Like JMV180, PD
170292 (6) acts as an antagonist at the CCK2 receptor.
It was unable to promote [Ca2+]i mobilisation in Jurkat
cells12 even at a concentration as high as 1 mM. How-
ever, it was able to antagonise the e€ects of CCK-8S on
[Ca2+]i accumulation (IC50 40Æ10 nM). Interestingly,
these ®ndings clearly contrast with those published for 5
which was found to be an agonist at both the CCK1 and
CCK2 receptor types.8
9. Sankaran, H.; Gold®ne, I. D.; Bailey, A.; Licko, V.; Wil-
liams, J. A. Am. J. Physiol. 1982, 242, G250.
10. Sankaran, H.; Gold®ne, I. D.; Deveney, C. W.; Wong, E.
Y.; Williams, J. A. J. Biol. Chem. 1980, 255, 1849.
11. Martinez, J.; Galas, M. C.; Lignon, M. F.; Rodriguez, M.;
Fulcrand, P. In CCK Antagonists in Gastroenterology, Adler
G.; Beglinger, C., Eds.; Springer: Berlin, Heidelberg, 1991; pp
80±90.
Conclusions
12. Lignon, M. F.; Galas, M. F.; Rodriguez, M.; Martinez, J.
Cellular Signalling 1990, 2, 339.
In this paper we have demonstrated the design and
synthesis of a novel, non-peptide CCK1 receptor ago-
nist. PD 170292 (6) behaves as a full agonist at the high
anity sites and as an antagonist at the low anity sites
of the CCK1 receptor. In addition to demonstrating
both high ecacy and potency for the CCK1 receptor
13. IC50 represents the concentration producing half-maximal
inhibition of speci®c binding of [125I] Bolton-Hunter CCK-8S
to CCK receptors in the mouse cortex (CCK2) or rat pancreas
(CCK1). Values given represent the arithmetic mean from at
least 3 experiments. For full experimental details see ref 6.
14. Jensen, R. T.; Lemp, G. F.; Gardner, G. D. J. Biol. Chem.
1982, 257, 5554.
15
type, compound 6 has also been shown to be a high
anity CCK2 receptor antagonist.
15. Physical data for compound PD 170292 (6): mp 109±112 ꢁC
(heptane±ethyl acetate); [a]2d1 6.8ꢁ (c 0.5 in CH2Cl2); analysis
C38H49N5O6 requires C, 67.93; H, 7.35; N, 10.42% found: C,
Acknowledgements
1
67.90; H, 7.60; N, 9.50%;nmax (®lm)/cm 3334, 1714, 1652,
1539, 1248; dH (DMSO-d6) 1.13.47 (11H, m, two of adamantyl-
H, CH3 and (CH2)3), 1.68.79 (8H, m, eight of adamantyl-H),
1.96 (4H, bs, four of adamantyl-H), 2,16 (3H, s, ArCH3),
2.22.36 (2H, m, CH2CO2H), 3.00 (2H, m, CH2NH), 3.19 (1H,
d, IndCHH, J 14.8 Hz), 3.41 (1H, d, IndCHH, J 14.8 Hz), 4.02
(1H, bs, CH2CH), 4.68 (1H, bs, CHOCONH), 6.53 (1H, t,
CONHCH, J 5.2 Hz), 6.70 (1H, bs, CH2NH), 6.82±7.10 (6H,
m, Ar-H and CHOCONH), 7.30 (1H, d, Ar-H, J 8.0 Hz), 7.46
(1H, d, Ar-H, J 8.0 Hz), 7.52 (1H, d, Ar-H, J 8.0 Hz), 7.55 (1H,
bs, ArNH), 7.81 (1H, d, Ar-H, J 8.4 Hz) and 10.86 (1H, s,
IndNH), 12.17 (1H, bs, CO2H); HRMS calculated for
C38H50N5O6 672.3761 (MH+) found 672.3757.
The authors wish to thank Nirmala Suman-Chauhan
and Louise Webdale for carrying out the CCK receptor
binding assays.
References and Notes
1. For a recent review see Pritchard, M. C.; Raphy, J.; Singh,
L. Exp. Opin. Invest. Drugs 1997, 6, 349.
2. (a) For an up to date review including studies on CCK1
receptor agonists see de Tullio, P.; Delarge, J. D.; Pirotte, B.