Discovery of pyrimidine carboxamides as potent and selective CCK1 receptor agonists

Article abstract of DOI:10.1016/j.bmcl.2011.03.069

A series of six-membered heterocycle carboxamides were synthesized and evaluated as cholecystokinin 1 receptor (CCK1R) agonists. A pyrimidine core proved to be the best heterocycle, and SAR studies resulted in the discovery of analog 5, a potent and struc

Full text of DOI:10.1016/j.bmcl.2011.03.069

Bioorganic & Medicinal Chemistry Letters 21 (2011) 2911–2915
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of pyrimidine carboxamides as potent and selective CCK1
receptor agonists
Liping Wang a, , James A. Hubert c, Susan J. Lee c, Jie Pan b, Su Qian b, Marc L. Reitman b, Alison M. Strack c,
⇑
Drew T. Weingarth b, Douglas J. MacNeil b, Ann E. Weber a, Scott D. Edmondson a
a Department of Medicinal Chemistry, Merck & Co. Inc., PO Box 2000, Rahway, NJ 07065, USA
b Department of Metabolic Disorders, Merck & Co. Inc., PO Box 2000, Rahway, NJ 07065, USA
c Department of Pharmacology, 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:
A series of six-membered heterocycle carboxamides were synthesized and evaluated as cholecystokinin 1
receptor (CCK1R) agonists. A pyrimidine core proved to be the best heterocycle, and SAR studies resulted
in the discovery of analog 5, a potent and structurally diverse CCK1R agonist.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 31 January 2011
Revised 15 March 2011
Accepted 17 March 2011
Available online 31 March 2011
Keywords:
Cholecycstokinin 1 receptor
CCK1R agonists
Pyrimidine
Carboxamide
Obesity is increasingly prevalent both in the United States and
globally. Excess weight and obesity lead to serious health conse-
quences including cardiovascular disease, diabetes, osteoarthritis,
sleep apnea, and certain cancers.1,2 Cholecystokinin (CCK) is the
major hormone responsible for gallbladder contraction and pan-
creatic enzyme secretion. CCK receptors have physiological roles
in stimulation of pancreatic and biliary secretions, regulation of
gastrointestinal mobility, postprandial inhibition of gastric empty-
ing, and regulation of food intake. Two different CCK receptors
have been identified that mediate the biological actions of CCK:
in the CCK1 receptor (formerly CCKAR) and the CCK2 receptor (for-
merly CCKBR). Biological actions mediated by the CCK1R suggest
that CCK1R agonists may be used for the treatment of obesity.3,4
Efforts to produce CCK1R agonists for treating obesity, resulted
in the discovery of 1,5-benzodiazepines GI181771X (1) and CE-
326597 (2), as well as thiazole SR-146131 (3)5–7 (Fig. 1). A Phase
II clinical trial with 1 resulted in no body weight loss in obese pa-
tients after 24 weeks of treatement.5 Nevertheless, combination
therapy with other anorectic agents was suggested by the authors
as a potential means to improve efficacy of this CCK1R agonist.
Imidazole carboxamides (e.g., 4 in Fig. 1) have been reported as
potent and selective CCK1R agonists that exhibit in vivo activity in
mice typical of CCK1R agonists such as gallbladder emptying and
overnight food intake reduction.8 SAR studies within this series
showed that the imidazole ring was the optimal five-membered
ring heterocyclic core for CCK1R agonist activity. In order to ex-
pand the structural diversity of this new series of CCK1R agonists,
we sought to replace the five-membered ring heterocyclic core
with six-membered ring heterocycles. Herein, we report the syn-
thesis and optimization of a series of six-membered ring heterocy-
cles designed to replace the imidazole core of 4. Ultimately, a series
of pyrimidine carboxamides (5 and 6) were discovered that dem-
onstrate potent and selective activity as CCK1R agonists.
The synthesis of pyrazines 28 and 29 (Fig. 2) is described in
Scheme 1. Commercially available 3-methoxy phenylacetic acid
was reacted with methyl p-toluate in the presence of lithium
bis(trimethylsilyl)amide to give ketone 8.9a Oxidation of the ben-
zylic methylene with selenium dioxide in acetic acid at 145 °C pro-
vided diketone 9,9b which was cyclized with 2-aminoacetamide to
afford both regioisomers 10 and 11.9b Treatment with phosphorus
oxychloride in toluene furnished pyrazine chlorides 12 and 13,9c
which were converted to carboxylic esters 14 and 15 using a palla-
dium mediated carbonylation reaction.9d Saponification of the es-
ters followed by coupling of the resulting acids with 3-naphthyl
piperazine yielded the two pyrazine derivatives which were sepa-
rated using a ChiralCel AD column to give 28 and 29.
The preparation of 3-pyridine carboxylic amide 30 is outlined in
Scheme 2. Intermediate 8 was reacted with DMF dimethyl acetal to
give vinylogous amide 16. Treatment of 16 with cyanoacetamide
and sodium hydride in DMF effected ring closure to the 5,6-dia-
ryl-3-cyanopyridine-2-one 17, which was converted to chloride
⇑
Corresponding author.
E-mail address: liping_wang@merck.com (L. Wang).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.03.069

2912
L. Wang et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2911–2915
Ph
N
Me
Me
N
O
O
O
N
H
N
H
N
O
N
N
N
O
O
N
CO2H
2
N
H
N
Ph
1
OEt
S
N
Me
HN
O
OMe
Cl
N
COOH
N
N
N
N
Me
Me
HO2C
O
4
MeO
3
O
COOH
COOH
O
MeO
Me
N
N
N
N
N
N
N
N
O
Me
F
O
F
5
6
Figure 1. CCK1R agonists GI181771X (1), CE-326597 (2), SR-146131 (3), imidazole carboxamide (4) and pyrimidine carboxamides (5 and 6).5–8
18 using phosphorus oxychloride in toluene. Conversion of nitrile
18 to the corresponding carboxylic acid was achieved by heating
with sulfuric acid, and the methyl ester 1910 was then formed by
treatment with diazomethane. Hydrogenation to remove the chlo-
ride then afforded 20. Saponification followed by coupling with 3-
naphthyl piperazine yielded pyridine analog 30.
Scheme 3 describes the synthesis of 2-pyridine carboxylic
amide 31. Cinnamic acid 21 was converted to the corresponding
aldehyde in a two step process via reduction to the alcohol fol-
lowed by oxidation to aldehyde 22. The aldehyde was reacted with
azidoacetate to give azido intermediate 23 which was then reacted
with triphenylphosphine in ether to yield intermediate 24. Subse-
quent cyclization with p-tolualdehyde in acetonitrile afforded pyr-
idine carboxylic ester 25.10 Saponification followed by coupling
with 3-naphthyl piperazine then furnished the 3-pyridine analog
31 (Fig. 2).
The synthesis of 5,6-diaryl pyrimidine carboxamide derivatives
is outlined in Scheme 4. Enamide 16 was reacted with acetamidine
in the present of sodium ethoxide to yield methyl pyrimidine 26.
The methyl group was next oxidized using selenium oxide in pyr-
idine to give the corresponding acid 27.11 Exposure of the aryl
piperazines with acid 27 under standard amide bond coupling con-
ditions then afforded diaryl pyrimidine derivatives 5, 6, and 33–57.
The in vitro human CCK1R binding activities8 of various six-
membered heterocyclic carboxamides 28–32 are displayed in Fig-
ure 2. The pyrazine 5-carboxamide 28 and pyridine 5-carboxamide
30 display insignificant binding affinity for the CCK1 receptor (IC50
>10
lM), while the pyrazine 6-carboxamide 29 possesses modest
potency (IC50 = 2.9
lM). In contrast, pyridine 6-carboxamide 31
and pyrimidine 2-carboxamide 32 are significantly more potent
at CCK1R binding. The substitution pattern on the six-membered
ring heterocyclic core plays an important role for CCK1R binding
potency. It appears that three contiguous moieties are important
for maintaining CCK1R potency: the para-methyl phenyl substitu-
ent, the embedded nitrogen in the six-membered ring heterocycle
core, and the carboxamide substituent. Although the origin of
these receptor/ligand relationships is not well understood, it is
noteworthy that this is consistent with SAR reported in the five-
membered ring cores.8a Both 31 and 32 provided excellent lead
structures for the development of novel CCK1R agonists, but only
the pyrimidine analogs (i.e., 32) were further pursued due to
CCK1R potency, synthetic accessibility, and the paucity of patent
publications on this structure class.
OMe
OMe
OMe
O
O
N
N
R
R
R
N
N
N
O
28
30
29
Me
Me
Me
CCK1R IC50 = >10,000 nM
CCK1R IC50 = 2,925 nM CCK1R IC50 = >10,000 nM
OMe
OMe
N
R =
N
N
Early structure–activity studies of CCK1R agonists in the imid-
azole carboxamide structure class identified the 3-quinoline as a
preferred piperazine substitutent.8 Consequently, this moiety was
maintained in SAR studies of the pyrimidine series in order to
properly evaluate the relative potencies of these compounds.
Initially, our efforts focused on optimization of the C-5 aromatic
group Ar1 (Table 1). Various 2-, 3- and 4-substituted phenyl deriv-
atives were prepared which included methoxyphenyl (33, 34, 36),
R
N
R
N
O
O
Me
Me
31
32
CCK1R IC50 = 35 nM
CCK1R IC50 = 33 nM
Figure 2. Binding affinities for six-membered heterocyclic aromatic carboxamides
at the human CCK1R. IC50s are an average of P2 assays with a standard deviations
<78%. See Supplementary data for assay protocols.14

L. Wang et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2911–2915
OMe
2913
OMe
OMe
c
a
b
O
O
O
OH
O
7
8
9
OMe
OMe
OMe
OMe
d
N
N
+
+
N
N
N
N
O
N
N
Cl
Cl
O
10
11
12
13
OMe
OMe
+
N
N
N
N
COOn-Bu
f, g
e
29
+
28
COOn-Bu
14
15
Scheme 1. Synthesis of 1,2-diaryl pyrazine carboxamides. Reagents: (a) methyl p-toluate, LiHMDS, THF (72%); (b) SeO2, AcOH,
D
(71%); (c) 2- aminoacetamide, NaOH, EtOH
(53%); (d) POCl3, toluene,
Chiral AD column (34%).
D (73%); (e) n-BuOH, CO gas, PdCl2(dppf), NEt3 (95%); (f) LiOH, MeOH; (g) substituted piperazine, EDC, HOBt, iPr2NEt, DMF, separation of isomers by
OMe
OMe
OMe
CN
Cl
b
a
CN
O
C
N
8
N
O
N
16
17
18
OMe
OMe
g-h
f
30
d-e
COOMe
COOMe
Cl
N
N
19
20
Scheme 2. Synthesis of 1,2-diaryl pyridine 4-carboxamide. Reagents: (a) 2-cyanoacetamide, DMF-acetal, DMF (100%); (b) 2-cyanoacetamide, NaH, MeOH, DMF (66%); (c)
POCl3, toluene,
D (64%); (d) 50% H2SO4, D; (e) TMSCN2, MeOH (55%, two steps); (f) PdCl2, MeOH (83%); (g) LiOH, THF, water, MeOH; (h) substituted piperazine, EDC, HOBt,
iPr2NEt, DMF.
OMe
OMe
OMe
COOMe
N3
c
a-b
OH
H
O
O
21
22
23
OMe
OMe
f, g
e
31
d
COOMe
N
COOMe
N
PPh
Me
24
25
Scheme 3. Synthesis of 1,2-diaryl pyridine 5-carboxamides. Reagents: (a) isopropyl chloroformate, NEt3, NaBH4, THF (51%); (b) Swern oxidation; (c) methyl diazoacetate in
DCM, NaOMe, MeOH; (d) PPh3, ether, p-tolualdehyde; (e) AcCN, (7%, three steps); (f) LiOH, MeOH; (g) 3-naphthyl piperazine, EDC, HOBt, iPr2NEt, DMF (37%, two steps).
D

2914
L. Wang et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2911–2915
Table 2
R1
R1
4-Pyrimidyl substituent (Ar2) modifications
c
a
b
N
N
16
5, 6, 33 - 57
MeO
N
N
COOH
N
R2
R2
N
N
26
N
27
Ar2
N
O
Scheme 4. Synthesis of 5, 6-diaryl pyrimidine carboxamides. Reagents: (a)
acetamidine, NaOEt in 20% EtOH, EtOH; (b) SeO2, pyridine,
D
; (c) substituted
piperazine, EDC, HOBt, iPr2NEt, DMF.
Ar2
EC50 (nM)
% Act.
IC50 (nM)
a
b,c
Compd
36
41
42
43
44
45
46
47
48
4-MePh
Ph
1.3
6.1
37
196
61
97
101
96
86
105
72
103
92
98
2.4
17.9
55
174
35
Table 1
5-Pyrimidyl substituent (Ar1) modifications
2-MePh
3-MePh
2-ClPh
3-FPh
4-FPh
2-FPh
N
38
51
Ar1
1.8
0.71
0.24
6.7
1.4
0.26
N
N
N
N
2-F,4-MePh
O
a
CCK_IP3 (IP3 assay of a CHO cell line expressing human CCK1R) agonist data,8
Me
values are means of P2 experiments, with standard deviations <77% of the average.
b
Values are an average of P2 experiments with standard deviations <75% of the
average.
c
See Supplementary data for binding assay protocols.14
Ar1
EC50 (nM)
% Act.
IC50 (nM)
a
b,c
Compd
33
34
35
36
37
38
39
40
2-MeOPh
3-MeOPh
3-EtOPh
4-MeOPh
286
42
34
1.3
21
256
88
94
165
35
25
2.4
2.4
857
1632
0.18
102
100
97
92
83
Table 3
5-Pyrimidyl substituent (Ar3) modifications
4-EtOPh
3,4-(MeO)2Ph
3,4-(HO)2Ph
3,4-(OCH2CH2O)Ph
MeO
90
91
0.73
Ar3
N
N
CCK_IP3 (IP3 assay of a CHO cell line expressing human CCK1R) agonist data,8
values are means of P3 experiments, with standard deviations <77% of the average.
a
N
N
b
Values are an average of P3 experiments with standard deviations <75% of the
O
average.
Me
See Supplementary data for assay protocols.14
c
ethoxyphenyl (35, 37), 3,4-dimethoxyphenyl 38, 3,4-dihydroxy-
phenyl 39 and 3,4-dioxanephenyl 40. The 4-methoxyphenyl analog
36 displays the most potent in vitro profile of the mono-substi-
tuted derivatives. This is a departure from the imidazole carbox-
amides where the 3-ethoxyphenyl substituent was optimal.
Interestingly, the disubstituted 1,4-benzodioxane derivative 40
dramatically improves CCK1R in vitro potencies, affording a 13-
fold improvement in functional activity and a two-fold improve-
ment in binding activity relative to the corresponding 4-methoxy-
phenyl compound 36.
a
b,c
Compd
R1
EC50 (nM)
% Act.
IC50 (nM)
49
50
51
52
53
54
55
56
57
Naphthyl-2-yl
Isoquinoline-3-yl
Quinoline-6-yl
1-Benzofuran-6-yl
1H-Indole-6-yl
Methyl-2-naphthate-3-yl
2-Naphthoic acid-3-yl
Methyl-1-naphthate-3-yl
1-Naphthoic acid-3-yl
27
17
7.5
10
41
105
115
86
91
91
78
94
95
104
16.9
13
19
9.9
66
587
95
4.7
2.0
5020
59
9.6
0.20
Selected modifications to the C-6 aromatic substituent (Ar2) in
the pyrimidine series were also evaluated (Table 2). The 4-fluoro-
phenyl derivative 46 displays minimal loss of CCK1R functional
and binding activity relative to the 4-methylphenyl derivative 36,
while the 2-fluorophenyl derivative 47 displays approximately a
two-fold improvement in both potencies. The 2-fluoro-4-methyl-
phenyl derivative 48 possesses the best overall in vitro profile in
this series, with excellent functional and binding activities at the
CCK1 receptor (EC50 = 0.24 nM, IC50 = 0.26 nM).
It was previously reported by our laboratories that quinoline-3-
yl and 1-naphthoic acid-3-yl piperazine amides in the imidazole
carboxamide structure class afforded excellent potency in CCK1R
functional and binding activities.8 This effect was also observed
with the 5,6-diarylpyrimidine 2-carboxamides (Table 3). Although
incorporation of a variety of biaryl groups is well tolerated, quino-
line-3-yl (36) and 1-naphthoic acid-3-yl (57) remain the optimal
aryl substituents. Indeed, analog 57 exhibits >10-fold increase in
potency compared to the corresponding naphthyl compound 49.
CCK_IP3 (IP3 assay of a CHO cell line expressing human CCK1R) agonist data,8
values are means of P3 experiments, with standard deviations <77% of the average.
a
b
Values are an average of P3 experiments with standard deviations <75% of the
average.
See Supplementary data for binding assay protocols.14
c
Combining all of the optimal substituents with the pyrimidine
carboxamide core resulted in analogs 5 and 6, which demonstrate
excellent functional and binding activities at the human CCK1R
(Table 4). Furthermore, these analogs exhibit potent functional
activity and full receptor activation at the mouse CCK1R (Table
4). Representative compound 5 was further evaluated in an
in vivo mouse gallbladder emptying (mGBE) assay in order to con-
firm a pharmacodynamic effect typical of CCK1R agonists.6a,8,14 At
an oral dose of 0.3 mg/kg, compound 5 reduced mouse gallbladder
weight by 63% compared with vehicle. In a second study, the over-
night food intake (ONFI) of lean mice dosed orally with 5 was mea-
sured relative to those dosed with vehicle.8 This compound

L. Wang et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2911–2915
2915
Table 4
3. Kopelman, P. G. Nature 2000, 404, 635.
Compounds 5 and 6 in vitro activities at human and mouse CCK1 receptorsa,b,14
4. (a) Kissileff, H. R.; Pi-Sunyer, X.; Thornton, J.; Smith, G. P. Am. J. Clin. Nutr. 1981,
34, 154; (b) Moran, T. H.; Ameglio, P. J.; Peyton, H. J.; Schwartz, G. J.; MuHugh, P.
R. Am. J. Physiol. 1993, 265, R620.
Compd hEC50
(nM)
% Act.
IC50
mEC50
(nM)
% Act.
hCCK1R
(nM)
hCCK1R
5. (a) Henke, B. R.; Aquino, C. J.; Croom, L. S.; Dougherty, R. W., Jr.; Ervin, G. N.;
Grizzle, M. K.; Hirst, G. C.; James, K. K.; Johnson, M. F.; Queen, K. L.; Sherrill, R.
G.; Sugg, E. E.; Suh, E. M.; Szewczyk, J. W.; Unwalla, R. J.; Yingling, J.; Willson, T.
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P.; Murphy, K.; Hill, J.; Kler, L.; Aftring, R. P. Clin. Pharmacol. Ther. 2007, 83, 281;
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Grizzle, M. K.; Hirst, G. C.; James, K. K.; Johnson, M. F.; Queen, K. L.; Sherrill, R.,
G.; Sugg, E. E.; Suh, E. M.; Szewczyk, J., W,; Unwalla, R. J.; Yingling, J.; Willson, T.
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Da Silva Jardin, P.; Dubins, J. S.; Gillaspy, M. A.; Hargrove, D. M.; Kalgutkar, A. S.;
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5
6
0.063
0.065
116
89
0.22
0.034
0.60
0.12
86
102
IP3 assay of a CHO cell line expressing mouse CCK1R,8 values are means of P2
experiments. Standard deviations are less than 70% of the mean.
Values are an average of P2 experiments with standard deviations <75% of the
average.
a
b
Table 5
Off-target activities of potent pyrimidine derived CCK1R agonists
Compd
IC50s (nM)
IKr
EC50 (nM)
CB2
CCK2R
Cox-1
5
6
>10,000
>10,000
>9000
>10,000
130
240
38 (À57%)
61 (À94%)
showed a significant effect on food intake reduction in mice at both
doses, affording a 95% reduction at 3 mg/kg and a 36% reduction at
0.3 mpk as compared with vehicle. The overall potency and effi-
cacy of 5 in these in vivo assays is comparable to that observed
with previously reported CCK1R agonist 4.8a
Selected off-target activities for potent CCK1R agonists 5 and 6
are illustrated in Table 5. Although the pyrimidine series shows
excellent selectivity over CCK2R binding, some of these com-
pounds are active as inhibitors of cyclooxygenase-1 (Cox-1)12
and as inverse agonists at the cannabinoid receptor type 2
(CB2).9a,13 For example, compound 5 showed an IC50 = 130 nM for
Cox-1 and an EC50 = 38 nM at À57% activation at the CB2 receptor.
In summary, the six-membered ring heterocyclic carboxamides
provide a diverse core for sub-type selective CCK1R agonists com-
pared to a previously reported imidazole carboxamide series. In or-
der to improve the potency of this new series of CCK1R agonists, it
was necessary to re-optimize the SAR of the substituents at both
Ar1 and Ar2. Ultimately, a pyrimidine series emerged that yielded
potent CCK1R agonists 5 and 6. Furthermore, analog 5 exhibited
potent pharmacodynamic activity characteristic of CCK1R agonists
in mice. Unfortunately, the discovery of some undesirable off-
target activities in this novel series of CCK1R agonists prevented
further development of these compounds.
Acknowledgments
The authors thank Dr. Richard Berger, Dr. Cheng Zhu, and
Ms. Amanda Makarewicz for intermediate scale-ups and paper
preparation. The authors acknowledge Stephanie Spann for assis-
tance with some of the in vivo studies.
10. Meurer, L. C.; Finke, P. E.; Mills, S. D.; Walsh, T. F.; Toupence, R. B.; Goulet, M. T.;
Tong, X.; Tung, M. F.; Lao, J.; Schaeffer, M.; Chen, J.; Shen, C.; Stribling, D. S.;
Shearman, L. P.; Strack, A. M.; Lex, H. T.; Goulet, M. T. Bioorg. Med. Chem. Lett.
2005, 15, 645.3.
11. Webb, T. R.; Moran, R.; Huang, C. Q.; McCarthy, J. R.; Grigoriadis, D. E.; Chen, C.
Bioorg. Med. Chem. Lett. 2004, 14, 3869.
12. (a) Hawkey, C. J. Best Pract. Res. Clin. Gastroenterol 2001, 15, 801; (b) Orjales, A.;
Mosquera, R.; Lopez, B.; Olivera, R.; Labeaga, L.; Nunez, T. M. Bioorg. Med. Chem.
2008, 16, 2183.
Supplementary data
13. (a) Han, S.; Thatte, J.; Jones, R. M. Ann. Rep. Med. Chem. 2009, 44, 227; (b)
Burdyga, G.; Lal, S.; Varro, A.; Dimaline, R.; Thompson, D.; Dockray, G. J.
Neurosci. 2004, 124, 2708; (c) Yan, L.; Huo, P.; Debenham, J. S.; Madsen-Duggan,
C. B.; Lao, J.; Chen, R. Z.; Xiao, J. C.; Shen, C.-P.; Stribling, D. S.; Shearman, L. P.;
Strack, A. M.; Tsou, N.; Ball, R.; Wang, J.; Tong, X.; Bateman, T. J.; Reddy, V. B.;
Fong, T. M.; Hale, J. J. J. Med. Chem. 2010, 53, 4028.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.03.069.
References and notes
14. Assay protocols are provided in Supplementary data. Activation of the CCK1
and CCK2 receptors are reported relative to 100% receptor activation.
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