Discovery of imidazole carboxamides as potent and selective CCK1R agonists

Article abstract of DOI:10.1016/j.bmcl.2008.06.057

High-throughput screening revealed diaryl pyrazole 3 as a selective albeit modest cholecystokinin 1 receptor (CCK1R) agonist. SAR studies led to the discovery and optimization of a novel class of 1,2-diaryl imidazole carboxamides. Compound 44, which was profiled extensively, showed good in vivo mouse gallbladder emptying (mGBE) and lean mouse overnight food intake (ONFI) reduction activities.

Full text of DOI:10.1016/j.bmcl.2008.06.057

Bioorganic & Medicinal Chemistry Letters 18 (2008) 4393–4396
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of imidazole carboxamides as potent and selective CCK1R agonists
a
d
d
a
c
Cheng Zhu a, , Alexa R. Hansen , Thomas Bateman , Zhesheng Chen , Tom G. Holt , James A. Hubert ,
Bindhu V. Karanam d, Susan J. Lee c, Jie Pan b, Su Qian b, Vijay B. G. Reddy d, Marc L. Reitman b,
Alison M. Strack c, Vincent Tong d, Drew T. Weingarth b, Michael S. Wolff a, Doug J. MacNeil b,
Ann E. Weber a, Joseph L. Duffy a, Scott D. Edmondson a
*
a Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co. Inc., PO Box 2000, Rahway, NJ 07065, USA
b Department of Metabolic Disorders, Merck Research Laboratories, Merck & Co. Inc., PO Box 2000, Rahway, NJ 07065, USA
c Department of Pharmacology, Merck Research Laboratories, Merck & Co. Inc., PO Box 2000, Rahway, NJ 07065, USA
d Department of Drug Metabolism, Merck Research Laboratories, 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:
High-throughput screening revealed diaryl pyrazole 3 as a selective albeit modest cholecystokinin 1
receptor (CCK1R) agonist. SAR studies led to the discovery and optimization of a novel class of 1,2-diaryl
imidazole carboxamides. Compound 44, which was profiled extensively, showed good in vivo mouse gall-
bladder emptying (mGBE) and lean mouse overnight food intake (ONFI) reduction activities.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 18 May 2008
Revised 13 June 2008
Accepted 17 June 2008
Available online 20 June 2008
Keywords:
CCK1R agonist
Obesity
Cholecystokinin
Food intake reduction
1,2-Diaryl imidazole
Cholecystokinin (CCK) is a peptide hormone secreted by the
duodenum in response to intraluminal nutrients (particularly fat
and protein). There are two CCK receptors, CCK1R and CCK2R (also
known as CCKA and CCKB receptors, respectively), which belong to
the G-protein coupled receptor (GPCR) superfamily. CCK1R stimu-
lation causes decreased food intake, delayed gastric emptying, in-
creased gallbladder emptying and increased pancreatic exocrine
secretion. CCK2R is the stomach gastrin receptor, mediating gastric
acid secretion, and is also widely expressed and functional in the
CNS.1
Me
Me
N
O
O
N
S
H
N
H
N
Me
HN
O
OMe
Cl
N
N
O
N
O
Me
HO2C
CO2H
MeO
1
2
Figure 1. CCK1R agonists GI181771X (1) and SR-146131 (2).
Since Gibbs et al. first demonstrated the satiety actions of CCK
in rats,2 CCK has been shown to inhibit food intake in multiple spe-
cies, including humans.3 CCK1R agonists, including peptides, pep-
toids, and small molecules, have been studied as satiety agents
for the treatment of obesity.4 Both the 1,5-benzodiazepine-based
GI181771X (1) and the thiazole SR-146131 (2) reached clinical tri-
als (Fig. 1).4 Recent phase II studies revealed that GI181771X (1)
alone did not cause weight loss in overweight or obese patients
after 24 weeks, and it was suggested that combination therapy
should be assessed in future studies.5a Tolerability-limiting gastro-
intestinal events including vomiting and diarrhea were observed,5
which might prohibit dosing at a level sufficient to cause robust
weight loss.
Through a high-throughput screening campaign, 1,5-diaryl pyr-
azole carboxamide 3 (Fig. 2) was identified as a selective albeit
OMe
Cl
B
CCK1R EC50 = 308 nM
D
5
%activation @ 10 uM = 82%
N
CCK1R IC50 = 41 nM
CCK2R inactive
(%activation @ 10 uM = 4.4%)
1N
N
A
N
3
C
Me
O
* Corresponding author. Tel.: +1 732 594 4497; fax: +1 732 594 5350.
E-mail address: cheng_zhu@merck.com (C. Zhu).
Figure 2. CCK1R agonist hit from high-throughput screening.
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.06.057

4394
C. Zhu et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4393–4396
modest CCK1R agonist.6,7 Herein, we describe the SAR studies
around this novel CCK1R agonist scaffold which led to the discov-
ery of a class of highly potent and selective CCK1R agonists.
SAR studies started with replacement of the central 1,5-diaryl
pyrazole core A with a variety of 5-membered heteroaromatic
rings. A series of isomeric pyrazoles, imidazoles, oxazoles, thia-
zoles, and triazoles were incorporated as cores in this system,
but only 1,2-diaryl imidazole 4 (Fig. 3) was found to have improved
potency relative to 3. All other heterocycles were less active
against CCK1R.
Table 1
Affects of D-ring modification Ar3
OMe
Ar3
N
N
N
N
Me
O
4, 8-18
Compound
Ar3
=
EC50 (nM)
IC50 (nM)
a,b
c
The synthesis of 1,2-diaryl imidazoles is outlined in Scheme 1.8
A variety of aryl groups Ar1 and Ar2 were incorporated into the
imidazole ring by condensing arylamidine 5 with 3-bromo-2-oxo-
propanoate in 1,4-dioxane or THF. After saponification, the result-
ing 1,2-diaryl-1H-imidazole carboxylic acid 6 was coupled with
aryl piperazine 7 either by EDC/HOBt or MsCl/1-methylimidazole
activation.9
Pd catalyzed C–N bond formation was utilized for the synthesis
of most non-commercially available aryl piperazines 7 (Scheme
2).10 For some aryl piperazines such as 2-piperazin-1-yl-1H-benz-
imidazole, direct nucleophilic aromatic substitution was utilized
(not shown).
The compounds synthesized were examined for their ability to
bind and activate CCK1R using a variety of in vitro assays.6 SAR
studies of Ar3 groups (Table 1) at the piperazine revealed that both
the agonist activity (EC50) and binding affinity (IC50) of 3,4-dichlo-
rophenyl 8 (EC50 = 25 nM, IC50 = 8.0 nM) were improved compared
with that of 4. Further improvements were noted with the 2-naph-
thyl piperazine derivative 9 (EC50 = 9.6 nM and IC50 = 2.5 nM)
while the 1-naphthyl derivative 10 was much less potent. Benz-
imidazole 11 had slightly reduced potency compared with the 2-
naphthyl derivative 9. For quinolines and isoquinolines 12–16,
4
8
9
3-ClPh
3,4-Cl2Ph
2-Naphthyl
1-Naphthyl
1H-Benzimidazol-2-yl
Quinolin-2-yl
Isoquinolin-3-yl
Quinolin-3-yl
Quinolin-6-yl
Isoquinolin-6-yl
2-Naphthoic acid-3-yl
1-Naphthoic acid-3-yl
74 (89% act)
25 (99% act)
9.6 (99% act)
5371 (30% act)
9.1 (89% act)
43 (89% act)
8.4 (89% act)
1.1 (92% act)
9.3 (108% act)
106 (86% act)
0.40 (92% act)
0.078 (85% act)
14
8.0
2.5
630
17
10
11
12
13
14
15
16
17
18
16
1.9
1.3
8.6
190
1.3
0.14
a
CCK_IP3 (CCK1 human, NFAT) agonist data, values are mean of P3 experiments
except compound 18 (n = 2), standard deviations are 682% of the mean. % Activa-
tion at 10,000 nM is given in parentheses.6
CCK2R inactive (% activations are 620% at 10,000 nM).6
Mean of P3 experiments, standard deviations are 692% of the mean.
b
c
the point of attachment had variable affects on CCK1R activities,
with quinoline 14 (EC50 = 1.1 nM, IC50 = 1.3 nM) being the most po-
tent. Carboxylic acid substitution on the naphthyl ring was next
explored. Acid 17 was found to possess improved potency
(EC50 = 0.40 nM, IC50 = 1.3 nM) relative to 9. Acid 18 afforded the
greatest improvement in both CCK1R functional and binding activ-
ities (EC50 = 0.078 nM, IC50 = 0.14 nM).
Since the 2-naphthyl compound 9 showed improved CCK1R
activities compared with the original 3-chlorophenyl derivative
4, SAR studies at the B and C rings were performed with 2-naph-
thylpiperazine derivatives (Tables 2 and 3). The crucial role of
the 3-alkoxy group on the B-ring is illustrated in Table 2 by com-
paring 9 (EC50 = 9.6 nM, IC50 = 2.5 nM) with the 3-ethyl analog 20
OMe
Cl
B
CCK1R EC50 = 74 nM
D
1
%activation @ 10 uM = 89%
N
N
CCK1R IC50 = 14 nM
CCK2R inactive
(%activation @ 10 uM = 9.6%)
2
A
N
N
C
Me
4
O
Figure 3. 1,2-Diaryl imidazole core with improved potency.
Table 2
Affects of B-ring modification Ar1
Ar1
Ar1
N
Ar1
NH
c
CN
b
a
Ar1NH2
Ar2
N
+
N
OEt
Ar2
Ar2
NH
N
N
5
N
O
Me
O
Ar1
N
Ar1
N
9, 19-28
Ar3
Ar3
N
N
d
+
a,b
c
OH
O
Ar2
N
Ar2
Compound
Ar1
=
EC50 (nM)
IC50 (nM)
HN
N
6
N
9
19
20
21
22
23
24
25
26
27
28
3-MeOPh
4-MeOPh
3-EtPh
3-HOPh
3-EtOPh
3-n-PrOPh
3-i-PrOPh
3-CF3OPh
3-CF3CH2OPh
9.6 (99% act)
20 (110% act)
65 (101% act)
82 (102% act)
6.6 (93% act)
962 (89% act)
53 (94% act)
3152 (66% act)
1349 (95% act)
0.99 (89% act)
471(70% act)
2.5
6.9
43
7
O
Scheme 1. Synthesis of 1,2-diaryl imidazole carboxamides. Reagents and condi-
tions: (a) NaHMDS, THF; (b) ethyl 3-bromo-2-oxopropanoate, NaHCO3, 1,4-dioxane
D; (c) NaOH, THF/MeOH/H2O; (d) EDC, HOBt, i-Pr2NEt or MsCl, 1-
methylimidazole.
22
2.3
160
30
or THF,
130
200
0.42
140
Ar3
P(Cy)2
Me2N
3,4-(OCH2CH2O)Ph
2,3-(OCH2CH2O)Ph
N
NH
a, b
Ar3Br
+
ligand:
HN
BocN
a
CCK_IP3 (CCK1 human, NFAT) agonist data, values are mean of P3 experiments,
standard deviations are 671% of the mean. % Activation at 10,000 nM is given in
parentheses.6
7
CCK2R inactive (% activations are 621% at 10,000 nM).6
b
Scheme 2. Synthesis of aryl piperazine 7. Reagents: (a) NaOt-Bu, Pd(dba)2, ligand;
(b) TFA, CH2Cl2.
c
Mean of P3 experiments, standard deviations are 686% of the mean.

C. Zhu et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4393–4396
4395
Table 3
Table 4
Affects of C-ring modification Ar2
Quinolin-3-yl and 1-naphthoic acid-3-yl with optimized Ar1 and Ar2
OEt
Ar1
N
Ar3
N
Ar3
=
N
Ar2
N
N
CO2H
N
N
O
N
Ar2
N
44-50
38-43
O
a,b
c,d
Compound
Ar1
Ar2
EC50 (nM)
IC50 (nM)
22, 29-37
38
39
40
41
42
43
44
45
46
47
48
49
50
3-EtOPh
3-EtOPh
3-EtOPh
3-EtOPh
3,4-(OCH2CH2O)Ph
3,4-(OCH2CH2O)Ph
3-EtOPh
3-EtOPh
3-EtOPh
3-EtOPh
4-MePh
4-FPh
2-FPh
2-F,4-MePh
4-MePh
4-FPh
4-MePh
4-FPh
2-F,4-MePh
2,4-F2Ph
4-MePh
4-FPh
0.73 (105%)
0.25 (92%)
0.53 (89%)
0.13 (86%)
0.12 (94%)
0.26 (101%)
0.094 (105%)
0.048 (95%)
0.056 (73%)
0.053 (76%)
0.14 (107%)
0.093 (97%)
0.077 (71%)
0.45
0.60
0.57
0.24
0.20
0.12
0.12
0.08
0.06
0.07
0.14
0.03
0.03
a,b
c
Compound
Ar2
=
EC50 (nM)
IC50 (nM)
22
29
30
31
32
33
34
35
36
37
4-MePh
Ph
4-EtPh
4-FPh
4-ClPh
3-FPh
2-FPh
2,6-F2Ph
2,4-F2Ph
2-F,4-MePh
6.6 (93% act)
7.4 (100% act)
175 (83% act)
2.9 (96% act)
5.5 (119% act)
105 (106% act)
6.3 (110% act)
4.4 (109% act)
1.1 (103% act)
1.9 (116% act)
2.3
3.4
43
1.9
5.6
35
1.9
1.9
1.0
0.56
3,4-(OCH2CH2O)Ph
3,4-(OCH2CH2O)Ph
3,4-(OCH2CH2O)Ph
2-F,4-MePh
a
CCK_IP3 (CCK1 human, NFAT) agonist data, values are mean of P3 experiments,
standard deviations are 666% of the mean. % Activation at 10,000 nM is given in
parentheses.6
a
CCK_IP3 (CCK1 human, NFAT) agonist data, values are mean of P3 experiments,
standard deviations are 672% of the mean. % Activation at 10,000 nM is given in
parentheses.6
CCK2R inactive (% activations are 612% at 10,000 nM).6
b
CCK2R inactive (% activations are 636% at 10,000 nM).6
b
c
Mean of P3 experiments, standard deviations are 668% of the mean.
c
Mean of P3 experiments, standard deviations are 688% of the mean.
d
CCK2R IC50 are >10,000 nM; % inhibitions are 624% at 10,000 nM.
(EC50 = 65 nM, IC50 = 43 nM). Additionally, the 4-methoxy com-
pound 19 was ꢀ2-fold less potent than the 3-methoxy derivative
9. Methoxy and ethoxy appeared to be optimal at the 3-position
of the B-ring as the 3-hydroxy (21), the 3-propoxy (23), and the
3-isopropoxy (24) derivatives were less potent than 9 and 22. Elec-
tron withdrawing alkyl groups connected to the 3-alkoxy position
such as OCF3 (25) and OCH2CF3 (26) also reduced the potency. The
biggest improvement in binding and functional activity was ob-
served with 1,4-benzodioxane compound 27 (EC50 = 0.99 nM,
IC50 = 0.42 nM) while regioisomer 28 was much less potent.
Next, the effects of ring C modification (Ar2 groups, Table 3)
were investigated. Unlike the B-ring which required a 3-alkoxy-
phenyl group for good potency, several different sterically small
substituents such as hydrogen (29), methyl (22), fluorine (31),
and chlorine (32) were well tolerated at the 4-position of the ring
C phenyl group. The 4-fluorophenyl compound 31 (EC50 = 2.9 nM,
IC50 = 1.9 nM) had slightly improved CCK1R activities compared
to 4-methyl 22 (EC50 = 6.6 nM, IC50 = 2.3 nM). Additionally, fluorine
substitution was also tolerated at the 2-position (34 and 35). The
2,4-disubstituted compounds 36 (EC50 = 1.1 nM, IC50 = 1.0 nM)
and 37 (EC50 = 1.9 nM, IC50 = 0.56 nM) had the most improved po-
tency. In contrast, 3-fluoro substitution (33) and more sterically
demanding substituents such as 4-ethyl (30) reduced potency
against CCK1R.
5). At an oral dose of 0.3 mg/kg, quinoline 38 reduced mouse gall-
bladder weight by 59% compared with vehicle (Table 5). However,
it was ineffective at an oral dose of 0.1 mg/kg. Much greater in vivo
mGBE activities were observed with the naphthoic acid derivatives
44, 45, 46, and 49 which all showed >50% reductions in gallbladder
weight at oral doses as low as 0.001 mg/kg (Table 5). Thus, carbox-
ylic acid substitution improved not only the in vitro CCK1R func-
tional and binding activities, but also the in vivo activities.
Compounds 44, sodium salt 44a (Fig. 4), 45, 46, and 49 also caused
robust overnight food intake (ONFI) reduction in lean mice at oral
doses of 3 mg/kg. Moreover, 44, 44a, 46, and 49 were effective at
oral doses of 0.3 mg/kg.12
At an oral dose of 10 mg/kg, compounds 44 and46 did not affect
overnight food intake in CCK1RÀ/À mice while inducing robust food
intake reduction in the wild type mice, indicating that the observed
food intake reduction with these compounds is CCK1R mechanism-
based.13 Although the food intake reduction observed in this
mouse model is CCK1R mediated, it is important to note that these
anorectic effects may not be solely attributed to an increased sati-
ety effect due to CCK1R activation.12 Nevertheless, the relative
magnitude of ONFI reduction provides a measurable method to
rank order CCK1R agonists’ effects in vivo.
After we discovered that quinolin-3-yl 14 and 1-naphthoic acid-
3-yl 18 (Table 1) improved CCK1R functional and binding activities
compared to 9, piperazines bearing these two aryl groups were
incorporated into the imidazole core with optimized B- and C-rings
(Table 4). Compounds 38–50 all possessed subnanomolar EC50 and
IC50 values. Furthermore, it was notable that they maintained
excellent selectivity over CCK2R.11 In general, the acid bearing
naphthalenes afforded superior in vitro profiles compared to the
quinoline derivatives, with 44–47, 49, and 50 all showing extre-
mely potent functional activity and binding at the CCK1 receptor.
One of the CCK1R agonist mediated physiological effects is the
stimulation of gallbladder emptying.1 Consequently, the in vivo
activities of CCK1R agonists presented here were first evaluated
in a mouse gallbladder emptying (mGBE) assay (see Supporting
Information). To facilitate interpretation of these data, mouse
CCK1R EC50 values of selected compounds were measured (Table
Table 5
In vivo mouse gallbladder emptying (mGBE) and lean mouse overnight food intake
(ONFI) reduction
b
Compounda
mEC50
(nM)
mGBEc,d
ONFI reductionc
po doses (mg/kg)
with >50% reduction
0.3 po at
mg/kg
3 po at
mg/kg
38
44
44a
45
46
49
2.1
1.3
0.78
1.5
0.30
0.14
0.3 (59%)
0.001 (72%)
—
0.001 (69%)
0.001 (77%)
0.001 (88%)
—
—
18%
29%
ns
13%
16%
82%
78%
73%
86%
96%
a
CF3COOH salts, except 44a which is sodium salt of 44.
Mouse CCK_IP3 agonist data, values are mean of P3 experiments. Standard
b
deviations are less than 70% of the mean.
c
Compared with vehicle (10% TweenÒ 80 in water), ns, not significant.
Mouse gallbladder weight % reduction is given in parentheses.
d

4396
C. Zhu et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4393–4396
OEt
Acknowledgments
The authors thank Richard Berger, Ramona Gray, and Amanda
Makarewicz for intermediates scale-up. The authors acknowledge
Stephanie Spann for the help of in vivo studies. The authors also
thank Tracy Johnson and Chris Nunes for dosing the animals used
in pharmacokinetic experiments. Alan Kopin at the Tufts University
School of Medicine is acknowledged for the use of CCK1RÀ/À mice.
N
CO2R
N
N
N
44: R = H
44a: R = Na
Me
O
Figure 4. Compound 44 (free acid) and sodium salt 44a.
Supplementary data
Table 6
Active in vivo CCK1R agonists pharmacokinetic profilea
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2008.06.057.
Compound
Species
Clp
(mL/min/kg)
Vd
(L/kg)
po AUCN
M h)
t1/2
(h)
F
(%)
Cmax
M)
(
l
(
l
44
44a
45
Mouse
Mouse
Mouse
Mouse
5.3
3.1
6.4
0.47
0.56
0.73
0.59
0.39
4.2
1.5
3.5
3.4
2.7
1.7
7
43
33
22
0.28
4.9
1.1
References and notes
1. Wank, S. A. Am. J. Physiol. 1998, 274, G607.
46
10.4
0.61
0.82
2. Gibbs, J.; Young, R. C.; Smith, G. P. J. Comp. Physiol. Psychol. 1973, 84, 488.
3. For recent reviews see (a) Little, T. J.; Horowitz, M.; Feinle-Bisset, C. Obes. Rev.
2005, 6, 297; (b) Moran, T. H.; Kinzig, K. P. Am. J. Physiol. Gastrointest. Liver
Physiol. 2004, 286, G183; (c) Chandra, R.; Little, T. J. Curr. Opin. Endocrinol.
Diabetes Obes. 2007, 14, 63; (d) Dufresne, M.; Seva, C.; Fourmy, D. Physiol. Rev.
2006, 86, 805.
aiv administration dosed at 1.0 mg/kg, po administration dosed at 10 mg/kg.
The mouse pharmacokinetic profiles of selected compounds are
shown in Table 6. Compound 45 had higher oral exposure and bio-
availability than 44, however, 45 was not more active in vivo to-
ward mouse ONFI reduction. It is notable that compounds 44
(mouse EC50 = 1.3 nM, % activity at 10
EC50 = 1.5 nM, % activity at 10 M = 101%) had similar in vitro
4. For lead CCK1R medicinal chemistry reviews see (a) Szewczyk, J. R.; Laudeman,
´
C. Curr. Top. Med. Chem. 2003, 3, 837; (b) Garcıa-López, M. T.; González-Mu ñiz,
´
´
R.; Martın-Martınez, M.; Herranz, R. Curr. Top. Med. Chem. 2007, 7, 1180.
5. (a) 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; (b) 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.
lM = 103%) and 45 (mouse
l
mouse CCK1R activities (Table 5). The sodium salt form 44a in-
creased the plasma exposure after an oral dose relative to the tri-
fluoroacetic acid salt of 44. Additionally, Cmax and oral
bioavailability increased. Paradoxically, however, 44a exhibited
similar ONFI reduction as the corresponding acid form 44. These
results suggest that systemic exposure of the compound may not
play an important role for in vivo efficacy.14
In conclusion, optimization of the heterocyclic core of HTS hit
3 led to the identification of a novel series of 1,2-diaryl imidaz-
ole carboxamides. Further optimization of the B, C, and D rings
led to the discovery of a class of highly potent and selective
CCK1R agonists. Quinoline 38 showed only modest in vivo mGBE
activity in spite of potent in vitro CCK1R functional and binding
activities. Introduction of a carboxylic acid group at the 1-posi-
tion of the naphthyl ring not only further improved the in vitro
profile, but most importantly also improved the in vivo CCK1R
mediated activities in mice such as gallbladder emptying and
overnight food intake reduction. Compounds 44, 44a, 46, and
49 all exhibited excellent in vivo mouse gallbladder emptying
(mGBE) activity and lean mouse overnight food intake (ONFI)
reduction. Since 44/44a (Fig. 4) showed a superior in vitro, in
vivo, and pharmacokinetic profile, this compound was selected
for extensive in vivo testing, and those results will be reported
in due course.
6. 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. All CCK1R EC50 values are human IP3 (NFAT) agonist data except
in Table 6 which are mouse CCK1R IP3 data. Both CCK1 and CCK2 % activation
are expressed as the
protocols are given in Supporting Information.
A series of 1,2-diary imidazoles have recently been reported as CCK1R
% of activation relative to CCK-8. Additional assay
7.
antagonists: (a) McClure, K.; Hack, M.; Huang, L.; Sehon, C.; Morton, M.; Li, L.;
Barrett, T. D.; Shankley, N.; Breitenbucher, J. G. Bioorg. Med. Chem. Lett. 2006, 16,
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11. CCK2R % activation and CCK2R % inhibition at 10,000 nM data for compounds
38–50 are given in Supporting Information.
12. No distinguishable behavioral features were noted between treatment and
vehicle control groups of the ONFI mice at both administered doses (0.3 and
3 mg/kg). Subsequent manuscripts describing the in vivo characteristics
(tolerability and efficacy) are in preparation.
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F.; Bonner-Weir, S.; Kanarek, R.; Beinborn, M. J. Clin. Invest. 1999, 103, 383.
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