2-Substituted piperazine-derived imidazole carboxamides as potent and selective CCK1R agonists for the treatment of obesity

Article abstract of DOI:10.1016/j.bmcl.2008.07.083

The discovery and structure-activity relationship of 1,2-diarylimidazole piperazine carboxamides bearing polar side chains as potent and selective cholecystokinin 1 receptor (CCK1R) agonists are described. Optimization of this series resulted in the disco

Full text of DOI:10.1016/j.bmcl.2008.07.083

Bioorganic & Medicinal Chemistry Letters 18 (2008) 4833–4837
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
2-Substituted piperazine-derived imidazole carboxamides as potent
and selective CCK1R agonists for the treatment of obesity
a
a
a
d
a
Richard Berger a, , Cheng Zhu , Alexa R. Hansen , Bart Harper , Zhesheng Chen , Tom G. Holt ,
James Hubert b, Susan J. Lee b, Jie Pan c, Su Qian c, Marc L. Reitman c, Alison M. Strack b, Drew T. Weingarth c,
Michael Wolff a, Douglas J. MacNeil c, Ann E. Weber a, Scott D. Edmondson a
*
a Department of Medicinal Chemistry, Merck & Co., Inc., 126 East Lincoln Ave., PO Box 2000, Rahway, NJ 07065-0900, USA
b Department of Pharmacology, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA
c Department of Metabolic Disorders, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA
d Department of Drug Metabolism & Pharmacokinetics, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The discovery and structure–activity relationship of 1,2-diarylimidazole piperazine carboxamides bear-
ing polar side chains as potent and selective cholecystokinin 1 receptor (CCK1R) agonists are described.
Optimization of this series resulted in the discovery of isopropyl carboxamide 40, a CCK1R agonist with
sub-nanomolar functional and binding activity as well as excellent potency in a mouse overnight food
intake reduction assay.
Received 23 May 2008
Revised 18 July 2008
Accepted 21 July 2008
Available online 24 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Cholecystokinin
CCK1R
Obesity
Imidazole carboxamides
The worldwide incidence of obesity is rising and has reached
epidemic levels in Western societies.1 In the United States, obesity
is a leading cause of morbidity and mortality, largely due to the in-
creased risk of type 2 diabetes mellitus, hypertension, dyslipide-
mia, cardiovascular disease, weight-bearing osteoarthritis, and
certain types of cancer.2,3
Cholecystokinin (CCK) is a peptide hormone secreted by the gut
in response to the ingestion of a meal. It promotes satiety and meal
termination, resulting in reduced meal size.4 This physiological ef-
fect has been observed in a variety of animal models, including hu-
mans, when CCK is administered prior to a meal.5–8 The CCK
peptide interacts with two G-protein coupled receptor subtypes:
the CCK1 receptor (CCK1R, also known as CCK-AR) and the CCK2
receptor (CCK2R, also known as CCK-BR).9 CCK2R is also the gastrin
receptor and is located primarily in the stomach and brain and reg-
ulates gastric acid secretion and many CNS related functions.9–11
CCK1R is found in the gallbladder, pyloric smooth muscle, and
the enteric vagal afferent nerves.5,11 Activation of CCK1R mediates
physiological effects including gallbladder contraction, gastric
emptying, intestinal motility, and satiety.6
closed in the literature (Fig. 1). The results of a phase II clinical trial
conducted with 1 were also reported.14 Although statistically sig-
nificant weight loss relative to placebo was not achieved in pa-
tients treated with 1, this lack of efficacy may be the result of
dose-limiting gastrointestinal adverse effects. Moreover, the
authors suggest that combination studies with other anorectic
agents could be used to maximize the benefits of a small molecule
CCK1R agonist.
Previous reports from our laboratories described the discov-
ery of imidazole carboxamides 3–5 as potent and selective
CCK1R agonists (Fig. 1).15 Optimization of this structure class
revealed that increasing agonist polarity often led to improved
CCK1R binding and functional activities. Based on these obser-
vations, the effect of appending polar substituents onto the
piperazine ring of compounds 3–5 was investigated. This letter
describes the synthesis and biological profile of
a series of
imidazole carboxamides represented by general structure
(Fig. 1).
6
The synthesis of a series of methylamine-linked derivatives be-
gan with an amide coupling between imidazole carboxylic acid
715b and the corresponding enantiomerically pure piperazine 8
employing mesyl chloride/1-methylimidazole activation (Scheme
1).16 The ester was subsequently reduced to the primary alcohol
with lithium borohydride, followed by acetylation with acetic
anhydride to afford 9. Removal of the N-carbobenzyloxy group
Two small molecule CCK1R agonists, 1,5-benzodiazepine
GI181771X (1)12 and thiazole SR-146131 (2),12b,13 have been dis-
* Corresponding author. Tel.: +1 732 594 3861; fax: +1 732 594 5790.
E-mail address: richard_berger@merck.com (R. Berger).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.07.083

4834
R. Berger et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4833–4837
N
O
O
N
H
N
H
N
S
N
HN
O
OMe
Cl
N
O
O
N
CO2H
1
2
HO2C
MeO
OEt
OEt
X
X
R
N
O
N
N
N
N
N
N
X = N, CCO2H
Y = H, F
N
O
3 X = N, Y = H
6
Y
Y
4 X =CCO2H, Y = H
5 X =CCO2H, Y = F
Figure 1. Small molecule CCK1R agonists for the treatment of obesity: GI181771X (1), SR-146131 (2), and Merck MRL imidazole carboxamides (3–6).
OAc
Ar2
Ar2
Cbz
MeO2C
+
Cbz
N
N
N
N
N
a-c
g- i
d, e
OH
Ar1
N
Ar1
HN
N
7
N
N
O
8
9
O
X
X
NH2
OR
Ar2
Ar2
N
N
N
X = N, CCO2Me
N
O
Ar1
N
Ar1
N
10 X =CCO2Me
18, 24 X = N
O
f
12
R =Ac
11 R =H, X = N, CCO2Me
R3
CO2H
R3
X
HN
O
HN
Ar2
Ar2
j or k
l
N
N
N
N
N
Ar1
N
Ar1
X = CCO2Me
N
N
13 X = CCO2Me
O
31-33, 37-39
20-22, 26, 27 X = N
Scheme 1. Synthesis of methylamine-linked derivatives: Ar1 = 4-MePh or 2-F,4-MePh, Ar2 = 3-EtOPh. Reagents and conditions: (a) MsCl, 1-methylimidazole, DMAP,
i
0 °C ? rt; (b) LiBH4, MeOH, 0 °C; (c) Ac2O, Pr2NEt, DMAP (65–76%, 3 steps); (d) 10% Pd/C, 40 psi H2, MeOH; (e) ArBr, Pd2(dba)3, Cs2CO3, 2-dicyclohexylphosphino-20-(N,N-
i
dimethylamino) biphenyl, 1,4-dioxane, 85 °C (75–80%, 2 steps); (f) NaOMe, MeOH, 0 °C (75–85%); (g) MsCl, Pr2NEt, CH2Cl2, 0 °C ? rt; (h) NaN3, DMF, rt; (i) 20% Pd(OH)2,
40 psi H2, MeOH (80–85%, 3 steps); (j) RSO2Cl or RCOCl, iPr2NEt, CH2Cl2, 0 °C ? rt (80–95%); (k) triphosgene, MeNH2, CH2Cl2, 0 °C (80%); (l) LiOH, THF/MeOH/H2O (90–95%).
with 10% palladium on activated carbon under an atmosphere of
hydrogen, followed by palladium-catalyzed C–N bond formation,
with either 3-bromoquinoline or methyl 3-bromo-1-naphthoate,
yielded compounds 10, 18, and 24.17 Subsequent removal of the
acetate with sodium methoxide revealed primary alcohol 11.
Amines 12 were prepared by initial mesylation of 11, followed
by nucleophilic displacement with azide and hydrogenation. Treat-
ment of 12 with an acid chloride or sulfonyl chloride in the pres-
ence of N, N-diisopropylethylamine afforded the desired CCK1R
agonists 20, 21, 26, and 27. Alternatively, 12 can be reacted with
triphosgene followed by methylamine to yield urea 22. In the case
of ester derivatives 13, a lithium hydroxide mediated saponifica-
tion was required to reveal the naphthoic acid derivatives 31–33
and 37–39.
A series of alkoxy acetic acids were also prepared from 11
(Scheme 2). Alkylation with bromo tert-butyl acetate in the pres-
ence of either sodium hydride or potassium carbonate, followed
by trifluoroacetic acid mediated deprotection of the ester afforded
the corresponding carboxylic acids 14, 19 and 25. Ester hydrolysis
of 14 revealed the bis-acids 30 and 36.
The preparation of the 2-piperazine carboxamides in the quin-
oline series began with an amide coupling between acid 715b and
the corresponding enantiomerically pure piperazine 1515b (Scheme
3). Saponification followed by
a 1-[3-dimethylamino)propyl]-

R. Berger et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4833–4837
4835
OH
X
X
OH
O
O
Ar2
Ar2
O
N
N
N
N
a or b
c
N
Ar1
N
Ar1
14 X = CCO2Me
19, 25 X = N
N
N
O
11
X = N, CCO2Me
CO2H
OH
O
Ar2
N
O
d
N
X = CCO2Me
N
Ar1
N
30, 36
O
Scheme 2. Synthesis of acetic acid-linked derivatives: Ar1 = 4-MePh or 2-F,4-MePh, Ar2 = 3-EtOPh. Reagents and conditions: (a) NaH tert-butyl bromoacetate, DMF, 0 °C; (b)
K2CO3, tert-butyl bromoacetate, DMF (70–80%, 2 steps); (c) TFA, CH2Cl2 (quantitative), (d) LiOH, THF/MeOH/H2O (90–95%).
N
N
NHR
N
Ar2
Ar2
O
MeO2C
+
N
a-c
N
N
N
Ar1
CO2H
HN
N
Ar1
23, 28 R = i-Pr
N
7
15
O
16 R =CH2CO2Me
29 R =CH2CO2H
d
Scheme 3. Synthesis of piperazine carboxamide derivatives: Ar1 = 4-MePh or 2-F,4-MePh, Ar2 = 3-EtOPh: (a) MsCl, 1-methylimidazole, DMAP, 0 °C ? rt (80–90%); (b) LiOH,
THF/MeOH/H2O; (c) EDC, HOAT, RNH2 (75–85%, 2 steps); (d) LiOH, THF/MeOH/H2O (90–95%).
CO2Me
CO2H
NHR
NHR
N
Ar2
Ar2
O
O
a, b
N
N
N
N
+
Ar1
CO2H
HN
N
Ar1
N
34, 35, 40
7
17
O
Scheme 4. Synthesis of piperazine carboxamide derivatives: Ar1 = 4-MePh or 2-F,4-MePh, Ar2 = 3-EtOPh: (a) MsCl, 1-methylimidazole, DMAP, 0 °C ? rt (80–90%); (b) LiOH,
THF/MeOH/H2O (90–95%).
Table 1
Selected 3-quinoline-derived CCK1R agonists
OEt
OEt
N
N
R1
R1
N
N
N
N
N
N
N
N
Me
Me
O
O
18-23
24-29
a
b,c
Compound
R1
H
EC50 (nM)
% Act.
IC50 (nM)
3
18
19
20
21
22
23
24
25
26
27
28
29
0.73
0.25
0.097
0.10
0.21
0.16
0.18
0.77
0.065
0.097
0.46
0.14
0.089
105
104
96
91
100
70
87
118
93
104
117
102
82
0.45
0.24
0.039
0.25
0.43
0.56
0.21
0.47
0.052
0.39
0.73
0.24
0.018
CH2OCOCH3
CH2OCH2CO2H
CH2NHCOCH3
CH2NHSO2Me
CH2NHCONHMe
CONHi-Pr
CH2OCOCH3
CH2OCH2CO2H
CH2NHCOCH3
CH2NHSO2Me
CONHi-Pr
CONHCH2CO2H
a
CCK_IP3 (CCK1 Human, NFAT) agonist data, values are means of P3 experiments, with standard deviations <75% of the average.
Values are an average of P3 experiments with standard deviations <75% of the average.
See Supporting information for binding assay protocols.
b
c

4836
R. Berger et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4833–4837
Table 2
Selected 3-(1-naphthoic acid)-derived CCK1R agonists
OEt
OEt
CO2H
CO2H
R2
R2
N
N
N
N
N
N
N
N
Me
Me
30-3
4
35
O
O
R2
EC50 (nM)
% Act.
IC50 (nM)
a
b,c
Compound
4
30
31
32
33
34
35
H
0.094
0.097
0.04
0.095
0.13
105
85
67
72
74
0.12
0.14
0.08
0.12
0.08
0.11
0.016
CH2OCH2CO2H
CH2NHCOCH3
CH2NHSO2Me
CH2NHCONHMe
CONHi-Pr
0.082
0.053
94
103
CONHi-Pr
a
CCK_IP3 (CCK1 Human, NFAT) agonist data, values are means of P3 experiments, with standard deviations <75% of the average.
Values are an average of P3 experiments with standard deviations <75% of the average.
See Supporting information for binding assay protocols.
b
c
3-ethylcarbodiimide (EDC)-mediated amide coupling afforded the
desired compounds 23 and 28. Hydrolysis of methyl ester 16 then
afforded glycine derivative 29.
25-fold boost in binding IC50 relative to the unsubstituted
parent 3.
Selected alterations in the 3-quinoline series were also incorpo-
rated into the 1-naphthoic acid derivative 4 with a minimal loss of
CCK1R activity (Table 2).18 For example, diacid 30 was almost iden-
tical to 4 in terms of CCK1R EC50 and IC50. Isopropyl carboxamide
35 possessed the best overall in vitro profile in this series, with
excellent functional activity and binding at the CCK1 receptor
(EC50 = 0.053 nM, IC50 = 0.016 nM).
It was previously reported that incorporation of a 2-fluoro-4-
methylphenyl moiety (5) improved CCK1R potencies in the 3-(1-
naphthoic acid) series.15 This effect was subsequently investigated
with the substituted piperazines (Table 3).18 These analogs main-
tained a similar in vitro profile to the parent 5, displaying excellent
potencies at the CCK1R in terms of functional activity and binding.
Compounds with superior activities at the CCK1 receptor were
evaluated for activity at the CCK2 receptor. Analogs 4, 5, 19, 29,
35, 37, and 40 all showed EC50s greater than 6000, nM and less
than 60% activation at the human CCK2R. Additionally, these ana-
logs showed binding IC50s > 10000 nM against the human CCK2R.19
The in vivo efficacies of these 2-substituted-piperazine-derived
imidazole carboxamides were also evaluated (Table 4). The over-
night food intake (ONFI) of lean mice, dosed orally with CCK1R
agonists at 0.3 and 3.0 mg/kg, was measured relative to those
dosed with vehicle.20 Similar to previous reports,15a neither of
the potent CCK1R agonists 19 or 29 in the 3-quinoline series exhib-
The naphthoic acid derivatives were prepared by first reacting
acid 715b with enantiomerically pure piperazine 1715b using mesyl
chloride/1-methylimidazole activation (Scheme 4). Methyl ester
saponification with lithium hydroxide yielded the desired CCK1R
agonists 34, 35, and 40.
The activities of selected 3-quinoline-derived CCK1R agonists
are reviewed in Table 1.18 Enantiomeric pairs generally had com-
parable EC50s and IC50s, with neither enantiomer showing signifi-
cantly greater CCK1R activity. Acetate 18 displayed improved
potency relative to 3, but was not pursued further due to the po-
tential metabolic liability of the ester functionality. Incorporating
similar polar functional groups such as sulfonamides, ureas, and
amides led to the identification of acetamides 20 and 26 as potent
CCK1R agonists. In addition, the incorporation of the glycine
carboxamide 29 afforded an 8-fold improvement in EC50 and a
Table 3
Effects of 2-fluoro,4-methylphenyl substituent in 3-(1-naphthoic acid) series
OEt
CO2H
R3
N
N
N
Table 4
N
Effect of orally dosed CCK1R agonists on 18-h overnight food intake reduction (ONFI)a
in mice
Me
36-40
O
F
Compound
mEC50 (nM)b
% Act.
Suppression of food intakea
a
b,c
R3
EC50 (nM)
% Act.
IC50 (nM)
@ 0.3 mpk
@ 3 mpk
Compound
4
5
1.30
0.30
0.50
0.11
0.11
0.13
0.034
103
56
84
99
110
77
18%
13%
nsc
82%
86%
nsc
5
36
37
38
39
40
H
0.055
0.034
0.033
0.10
0.074
0.071
73
106
70
97
90
0.040
0.041
0.058
0.067
0.097
0.010
CH2OCH2CO2H
CH2NHCOCH3
CH2NHSO2Me
CH2NHCONHMe
CONHi-Pr
19
29
35
37
40
nsc
nsc
19%
45%
18%
92%
nsc
94
94
32%
a
CCK_IP3 (CCK1 Human, NFAT) agonist data, values are means of P 3 experi-
a
Compared with vehicle (10% Tw80 in water).
CCK_IP3 (CCK1 Mouse, K1) agonist data, values are means of P 3 experiments,
ments, with standard deviations <75% of the average.
b
b
Values are an average of P3 experiments with standard deviations <75% of the
with standard deviations <75% of the average.
average.
c
c
ns, not significant.
See Supporting information for binding assay protocols.

R. Berger et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4833–4837
4837
Table 5
Effect of 40 on 18- and 48-h ONFIa in wild-type and CCK1Rꢀ/ꢀmice
References and notes
1. (a) Department of Health and Human Services, Center for Disease Control
and Prevention: ‘Overweight and Obesity’ http://www.cdc.gov/nccdphp/
dnpa/obesity/index.htm (2007).; (b) Balkau, B.; Deanfield, J. E.; Després, J.-
P.; Bassand, J.-P.; Fox, K. A. A.; Smith, S. C.; Barter, P.; Tan, C.-E.; Van
Gaal, L.; Wittchen, H.-U.; Massien, C.; Haffner, S. M. Circulation 2007, 116,
1942.
Mouse
Suppression of food intake @ 3 mpka
48 h
18 h
Wild-type
CCK1Rꢀ/ꢀ
89%
nsb
85%
nsb
2. (a) Adams, K. F.; Schatzkin, A.; Harris, T. B.; Kipnis, V.; Mouw, T.; Ballard-
Barbash, R.; Hollenbeck, A.; Leitzmann, M. F. N. Engl. J. Med. 2006, 335, 763; (b)
McTigue, K.; Larson, J. C.; Valoski, A.; Burke, G.; Kotchen, J.; Lewis, C. E.;
Stefanick, M. L.; Van Horn, L.; Kuller, L. JAMA 2006, 296, 79; (c) Katzmarzyk, P.
T.; Janssen, I.; Ardern, C. I. Obes. Rev. 2003, 4, 257.
a
Compared with vehicle (10% Tw80 in water).
ns, not significant.
b
Table 6
3. Venkat Narayan, K. M.; Boyle, J. P.; Thompson, T. J.; Sorensen, S. W.;
Williamson, D. F. JAMA 2003, 290.
Active in vivo CCK1R agonists mouse pharmacokinetic profilea
4. (a) Lieverse, R. J.; Jansen, J. B. M. L.; Masclee, A. A. M.; Lamers, C. B. H. W. Ann. NY
Acad. Sci. 1994, 713, 268; (b) Liddle, R. A.; Goldfine, I. D.; Rosen, M. S.; Taplitz, R.
A.; Williams, J. A. J. Clin. Invest. 1985, 75, 1144; (c) Kissileff, H. R.; Pi-Sunyer, F.
X.; Thornton, J.; Smith, G. P. Am. J. Clin. Nutr. 1981, 34, 154.
5. (a) Chandra, R.; Little, T. J. Curr. Opin. Endocrinol. Diabetes Obes. 2007, 14, 63; (b)
Dufresne, M.; Seva, C.; Fourmy, D. Physiol. Rev. 2006, 86, 805; (c) Moran, T. H.;
Kinzig, K. P. Am. J. Physiol. Gastrointest. Liver Physiol. 2004, 286, G183.
6. (a) Little, T. J.; Horowitz, M.; Feinle-Bisset, C. Obes. Rev. 2005, 6, 297; (b) Cox, J.
E.; Randich, A. Brain Res. 1997, 776, 189; (c) Moran, T. H.; Norgren, R.; Crosby, R.
J.; McHugh, P. R. Brain Res. 1990, 526, 95.
Compound Clp
(ml/min/kg)
Vd
(L/kg)
PO AUC
M-h)
t1/2
(h)
F
(%)
Cmax
M)
Tmax
(h)
(
l
(
l
4
5
35
40
5.3
10.4
20.4
9.7
0.47
0.59
3.7
0.39
0.61
0.15
0.1
3.5
1.7
2.5
2.3
7
0.28
6.7
0.6
5.5
8.0
22 0.82
11 0.18
0.42
4
0.18
a
IV administration dosed at 1.0 mpk, PO administration dosed at 10 mpk.
7. Gibbs, J.; Young, R. C.; Smith, G. P. J. Comp. Physiol. Psychol. 1973, 84, 488.
8. Gibbs, J.; Falasco, J. D.; McHugh, P. R. . Am. J. Physiol. 1976, 230, 12.
9. (a) Noble, F.; Wank, S. A.; Crawley, J. N.; Bradwejn, J.; Serogy, K. B.; Hamon, M.;
Roques, B. P. Pharmacol. Rev. 1999, 51, 745; (b) de Weerth, A.; Pisegna, J. R.;
Huppi, K.; Wank, S. A. Biochem. Biophys. Res. Commun. 1993, 194, 811.
10. (a) Chen, D.; Zhao, C. M.; Hakanson, R.; Samuelson, L. C.; Rehfeld, J. F.; Friis-
Hansen, L. Gastroenterology 2004, 126, 476; (b) Wank, S. A.; Pisegna, J. R.; de
Weerth, A. Ann. NY Acad. Sci. 1994, 713, 49.
ited any in vivo activity. On the other hand, compounds 4, 5, 35, 37,
and 40 containing the 3-(1-naphthoic acid) all displayed a statisti-
cally significant decrease in food intake relative to vehicle. Based
on these results, it seems that both incorporation and positioning
of the carboxylic acid moiety are critical factors that determine
the magnitude of in vivo potency in this structure class. The isopro-
pyl carboxamide 40 had the most significant effect on the reduc-
tion of overnight food intake in mice at both doses. Additionally,
at an oral dose of 3.0 mg/kg, 40 had no effect on food intake in
CCK1Rꢀ/ꢀ mice21 while inducing a significant reduction in food in-
take in wild-type mice (Table 5). Although these results indicate
that food intake reduction observed in wild-type mice dosed with
40 is CCK1R-mediated, it should be noted that the anorectic effects
may not be solely attributed to an increased satiety effect due to
CCK1R activation.22 Nevertheless, the ONFI reduction provides a
quantifiable method to evaluate the in vivo effects of CCK1R
agonists.
Table 6 presents the mouse pharmacokinetic profile of com-
pounds active in the ONFI assay. The most potent compound (40)
had the lowest oral exposure, oral bioavailability, and Cmax, sug-
gesting that systemic exposure may not be necessary for efficacy.23
In conclusion, a series of 2-substituted piperazine derived 1,2-
diarylimidazole carboxamides were found to be highly potent
and selective CCK1R agonists. Although several compounds pos-
sessed comparable sub-nanomolar in vitro activities, these activi-
ties did not always translate into in vivo efficacy. The
isopropylcarboxamide 40 exhibited one of the most potent in vitro
and in vivo profiles observed in this structure class to date.
11. Wank, S. A. Am. J. Physiol. 1998, 274, G607.
12. (a) García-López, M. T.; González-Muñiz, R.; Martín-Martínez, M.; Herranz, R.
Curr. Top. Med. Chem. 2007, 7, 1180; (b) Szewczyk, J. R.; Laudeman, C. Curr. Top.
Med. Chem. 2003, 3, 837.
13. Bignon, E.; Bachy, A.; Boigegrain, R.; Brodin, R.; Cottineau, M.; Gully, D.;
Herbert, J.-M.; Keane, P.; Labie, C.; Molimard, J.-C.; Olliero, D.; Oury-Donat, F.;
Petereau, C.; Prabonnaud, V.; Rockstroh, M.-P.; Schaeffer, P.; Servant, O.;
Thurneyssen, O.; Soubrié, P.; Pascal, M.; Maffrand, J.-P.; Le Fur, G. JPET 1999,
289, 742.
14. (a) Castillo, E. J.; Delgado-Aros, S.; Camilleri, M.; Burton, D.; Stephens, D.;
O’Connor-Semmes, R.; Walker, A.; Shachoy-Clark, A.; Zinsmeister, A. R. . Am. J.
Physiol. Gastrointest. Liver Physiol. 2004, 287, G363; (b) Jordan, J.; Greenway, F.
L.; Leiter, L. A.; Li, Z.; Jacobson, P.; Murphy, K.; Hill, J.; Kler, L.; Aftring, R. P. Clin.
Pharmacol. Ther. 2008, 83, 281.
15. (a) Zhu, C.; Hansen, A. R.; Bateman, T.; Chen, Z.; Holt, T. G.; Hubert, J. A.;
Karanam, B. V.; Lee, S. J.; Pan, J.; Qian, S.; Reddy, V. B. G.; Reitman, M. L.; Strack,
A. M.; Tong, V.; Weber, A.; Weingarth, D. T.; Wolff, M. S.; MacNeil, D. J.; Weber,
A. E.; Duffy, J. L.; Edmondson, S. D. Bioorg. Med. Chem. Lett. 2008, 18, 4393; (b)
Berger, R.; Edmondson, S. E.; Hansen, A. R.; Zhu, C. Substituted imidazole
4-carboxamides as cholecystokinin-1 receptor modulators. WO2007120688,
2007.
16. Ueki, H.; Ellis, T. K.; Martin, C. H.; Boettiger, T. U.; Bolene, S. B.; Soloshonok, V.
A. J. Org. Chem. 2003, 68, 7104.
17. Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 9722.
18. (a) Pan, J.; Weingarth, D. T.; Qian, S.; Morin, N.; Edmondson, S. D.; Zhu, C.;
Berger, R.; Hansen, A. R.; Lee, S. J.; Hubert, J. A.; Strack, A. M.; MacNeil, D. J., in
preparation; (b) All CCK1R EC50 values are human IP3 (NFAT) agonist data
except in Table 4 which are mouse CCK1R IP3 data. CCK1R % activations are
expressed as the % of activation relative to CCK-8. Additional assay protocols
are available in the Supporting information.
19. All CCK2R EC50 values are human IP3 agonist data and are an average of P3
experiments with standard deviations <75% of the average. CCK2 % activations
are expressed as the % of activation relative to CCK-8. CCK2R IC50s are an
average of P3 experiments with standard deviations <75% of the average.
Additional assay protocols are given in the Supporting information.
20. For a reference describing the ONFI studies in more detail: Lee, S. J.; Hubert, J.
A.; Edmondson, S. D.; Zhu, C.; Hansen, A. R.; Wolff, M. S.; Holt, T. G.; Karanam,
B. V.; Kumar, S.; Qian, S.; Weingarth, D. T.; Pan, J.; Weber, A. E.; MacIntyre, D. E.;
Strack, A. M.; MacNeil, D. J., manuscript in preparation.
21. Kopin, A. S.; Mathes, W. F.; McBride, E. W.; Nguyen, M.; Al-Haider, W.; Schmitz,
F.; Bonner-Weir, S.; Kanarek, R.; Beinborn, M. J. Clin. Invest. 1999, 103, 383.
22. GI tolerability findings consistent with diarrhea were observed in several of the
wild-type mice dosed with compound 40 (Table 5). There were no GI
tolerability findings observed with the CCK1Rꢀ/ꢀ mice. Subsequent
manuscripts describing the in vivo characteristics of selective CCK1R agonists
are currently in preparation.
Acknowledgments
The authors thank Ramona Gray and Amanda Makarewicz for
the scale-up of synthetic intermediates. The authors acknowledge
Tracy Johnson, Chris Nunes, Jim Hausamann, Bo Wang, and Lajla
de Reus for dosing the animals used in the pharmacokinetic exper-
iments. The authors also thank Alan Kopin at the Tufts University
School of Medicine for the use of CCK1Rꢀ/ꢀ mice.
Supplementary data
23. Sugg, E. E.; Birkemo, L.; Gan, L. L.; Tippin, T. K. Pharm. Biotechnol. 1998, 11, 507.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2008.07.083.