The discovery and optimization of pyrimidinone-containing MCH R1 antagonists

Article abstract of DOI:10.1016/j.bmcl.2006.07.008

Optimization of a series of constrained melanin-concentrating hormone receptor 1 (MCH R1) antagonists has provided compounds with potent and selective MCH R1 activity. Details of the optimization process are provided and the use of one of the compounds in

Full text of DOI:10.1016/j.bmcl.2006.07.008

Bioorganic & Medicinal Chemistry Letters 16 (2006) 4723–4727
The discovery and optimization of pyrimidinone-containing
MCH R1 antagonists
Donald L. Hertzog,* Kamal A. Al-Barazanji, Eric C. Bigham, Michael J. Bishop,
Christy S. Britt, David L. Carlton, Joel P. Cooper, Alex J. Daniels, Dulce M. Garrido,
Aaron S. Goetz, Mary K. Grizzle, Yu C. Guo, Anthony L. Handlon, Diane M. Ignar,
Ronda O. Morgan,ꢀ Andrew J. Peat, Francis X. Tavares and Huiqiang Zhou
Metabolic and Viral Diseases Centre of Excellence for Drug Discovery, GlaxoSmithKline, Five Moore Drive,
Research Triangle Park, NC 27707, USA
Received 11 May 2006; revised 26 June 2006; accepted 5 July 2006
Available online 25 July 2006
Abstract—Optimization of a series of constrained melanin-concentrating hormone receptor 1 (MCH R1) antagonists has provided
compounds with potent and selective MCH R1 activity. Details of the optimization process are provided and the use of one of the
compounds in an animal model of diet-induced obesity is presented.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Obesity has reached epidemic proportions in both the
United States and Western Europe. Obesity has been
linked to a number of comorbidities including type 2
diabetes, coronary artery disease, breast and colon
cancers, and hypertension. Clearly, effective therapies
to address obesity and its comorbidities are needed.
pursuit of MCH R1 antagonists for the treatment of
obesity.4
We have previously described the biphenyl amide MCH
R1 antagonist 1 and detailed its optimization first to the
constrained quinazolinone 2 and later to the thienopyri-
midinone 3.5 We report herein our efforts at further
development of structure–activity relationships (SAR)
within these thienopyrimidinone analogs.
The evidence for the potential use of melanin-concen-
trating hormone receptor antagonists, and MCH R1
antagonists in particular, as agents for the treatment
of obesity is significant. This evidence includes reports
that (1) intracerebroventricular (icv) administration of
MCH stimulates feeding in rodents;1 (2) fasting upregu-
lates MCH mRNA in both lean and obese animals;1 (3)
transgenic animals lacking MCH feed less, have reduced
body weight, and increased leanness relative to their
wild-type counterparts;2 and (4) transgenic animals de-
void of MCH R1 are resistant to diet-induced obesity.3
This evidence supporting a role for MCH in the regula-
tion of feeding and body weight has led to the active
OMe
OMe
O
N
O
O
N
N
O
N
N
H
1
2
OMe
O
N
O
N
S
N
3
Keywords: Melanin-concentrating hormone; MCH; MCH R1; MCH
antagonist; MCH R1 antagonist.
Modification of the left-hand aryl substituent was
accomplished through two different synthetic methods.
For compounds 5a–c, coupling of acid 46 with 3-meth-
oxy-4-(2-pyrrolidin-1-ylethoxy)aniline provided amide
5. Subsequent nitro reduction and treatment with reflux-
*
Corresponding author. Tel.: +1 919 483 5892; fax: +1 919 315
0430; e-mail: Donald.L.Hertzog@gsk.com
ꢀ
Present address: Bayer Pharmaceuticals Corporation, 400 Morgan
Lane, West Haven, CT 06516, USA.
0960-894X/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.07.008

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D. L. Hertzog et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4723–4727
OMe
O
O
S
Br
S
N
Br
CO2H
NO2
N
a
b, c
H
NO2
4
5
OMe
OMe
O
O
S
O
O
Ar
S
Br
d
N
N
N
N
N
N
7
6
i
S
S
O
e, f
g
h
CO2Me
Cl
Ar
Ar
CO2Me
NH2
CN
Ar CH3
Ar
N
NMe2
9
11
10
8
Scheme 1. Reagents and conditions: (a) 3-methoxy-4-(2-pyrrolidin-1-ylethoxy)aniline, HOBT, EtN(i-pr)2, CH2Cl2, 25 ꢁC, 72 h, 31%; (b) SnCl2ÆH2O;
EtOH, 78 ꢁC, 0.5 h; (c) formic acid, 100 ꢁC, 1 h, 42% (two steps); (d) ArB(OH)2, Pd(dppf)2Cl2, 1 M Na2CO3, EtOH, THF, 75 ꢁC, 0.5 h, 34-47%; (e)
POCl3, DMF, 0 ꢁC, 1 h; (f) hydroxylamine hydrochloride, 1 h, 0 ꢁC, 25–54% (two steps); (g) methyl mercaptoacetate, NaOMe, MeOH, 25 ꢁC, 10 min,
50–96%; (h) DMF–dimethyl acetal, DMF, 100 ꢁC, 15 h, 95–100%; (i) 3-methoxy-4-(2-pyrrolidin-1-ylethoxy)aniline, phenol, 140 ꢁC, 1.5 h, 46–65%.
ing formic acid (Scheme 1) provided pyrimidinone 6. Su-
zuki coupling with the appropriate boronic acid then
provided the desired analogs 7a–c.
Table 1. MCH R1 functional activity (pIC50) of thienopyrimidinone
analogs 48
OMe
O
O
The analogs 7d–r were prepared through a sequence
involving conversion of the acetophenone derivatives 8
to the corresponding nitriles 9. Thiophene formation
was then accomplished by treatment of the nitriles with
the sodium anion of methyl mercaptoacetate. Conver-
sion to the amidines 11d–r was followed by a convenient
cyclization with 3-methoxy-4-(2-pyrrolidin-1-yleth-
oxy)aniline to provide the pyrimidinones 7d–r (Scheme
1).7 Compound 7s was made from commercially avail-
able methyl 3-amino-2-thiophenecarboxylate (10s,
Ar = H) using the same two-step sequence described
for compounds 7d–r.
S
Ar
N
N
N
7
Compound
Ar
Ph
4-F-Ph
4-Cl-Ph
MCH R1 pIC50
7a
7b
7c
7d
7e
7f
8.7
8.9
9.3
9.0
8.6
7.9
7.7
5.9
8.3
5.5
8.2
8.8
7.6
8.3
6.7
5.8
7.6
7.0
5.4
4-OMe-Ph
4-CF3-Ph
4-NH2-Ph
4-CN-Ph
7g
7h
7i
4-SO2Me-Ph
4-NO2-Ph
The compounds were evaluated in a functional assay for
MCH R1 activity utilizing luciferase activity as a read-
out (Table 1).8 Several of the analogs substituted at
the 4-position of the aromatic ring proved to be more
potent than the unsubstituted phenyl analog 7a. These
compounds included the 4-flouro (7b, pIC50 8.9), 4-chlo-
ro (7c, pIC50 9.3), and 4-methoxy (7d, pIC50 9.0) deriv-
atives. It should be noted that not all of the 4-substituted
derivatives gained potency relative to 7a. Larger groups
at the 4-position of the aromatic ring proved especially
detrimental to activity (examples 7h,j). Small polar
groups such as amino, cyano, and nitro (examples
7f,g, and 7i, respectively) were not well tolerated. None
of the mono-substituted analogs with substitution at
either the 2- or 3-positions of the aromatic ring (exam-
ples 7k,m,n) proved to be as potent as the phenyl-substi-
tuted 7a. Several heteroaryl derivatives were synthesized
(examples 7o–r) and all of them had potencies less than
that of phenyl-substituted 7a. The preference for small,
lipophilic substituents in the 4-position of the aryl ring
suggests that the aryl ring may reside in a tight hydro-
phobic pocket within the receptor.
7j
4-NHCOCH3-Ph
3-Cl-Ph
7k
7l
3,4-DiCl-Ph
3-I-Ph
2-Cl-Ph
7m
7n
7o
7p
7q
7r
7s
4-Pyridinyl
3-Pyridinyl
3-Thiophene-yl
2-Thiophene-yl
H
gated. Thus, the furan, benzo, and thiazole analogs were
prepared with the remaining portions of the molecules
held constant.
Furan derivative 16 was synthesized as detailed in
Scheme 2. Using conditions adapted from those of Red-
man and co-workers, Mitsunobu reaction of 3-(4-chloro-
phenyl)-3-oxo-propanenitrile (12) with ethyl glycolate
was followed by sodium hydride-affected ring closure
to provide aminofuran 14.9 Treatment with DMF–
DMA provided amidine 15 which was then converted
to pyrimidinone 16 through heating with 3-methoxy-
4-(2-pyrrolidin-1-ylethoxy)aniline in ethanol at reflux.
An investigation into the effects of altering the five-
membered ring fused to the pyrimidinone was investi-

D. L. Hertzog et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4723–4727
4725
O
Cl
Cl
O
Cl
Cl
S
a
CN
b
a
Cl
b
S
S
OMe
NH2
O
CO2Et
O
CO2Et
NH2
N
Cl
N
S
CN
CN
22
23
24
c, d
12
13
14
c
OMe
OMe
O
Cl
O
Cl
O
Cl
O
O
d
N
CO2Et
S
O
N
N
N
N
N
NMe2
N
N
25
16
15
Scheme 4. Reagents and conditions: (a) (i) cyanamide, KOMe,
MeOH, 25 ꢁC, 3 h; (ii) MeI, DMF, 25 ꢁC, 2 h, 86% (two steps); (b)
methyl mercaptoacetate, Et3N, MeOH, 25 ꢁC, 24%; (c) DMF–
dimethyl acetal, 100 ꢁC, 3 h; (d) 3-methoxy-4-(2-pyrrolidin-1-yleth-
oxy)aniline, ethanol, 78 ꢁC, 18 h, 12%.
Scheme 2. Reagents and conditions: (a) PPh3, DIAD, THF, ethyl
glycolate, 25 ꢁC, 14 h, 34%; (b) NaH, THF, 25 ꢁC, 3 h, 85%; (c) DMF–
dimethyl acetal, 104 ꢁC, 6 h, 99%; (d) 3-methoxy-4-(2-pyrrolidin-1-
ylethoxy)aniline, ethanol, 78 ꢁC, 24 h, 44%.
Table 2. MCH R1 functional activity of B-ring analogs8
The benzo derivative 21 was synthesized as detailed in
Scheme 3. Coupling acid chloride 17 with 3-methoxy-
4-(2-pyrrolidin-1-ylethoxy)aniline provided compound
18 which was then reduced with stannous chloride to
provide amine 19. Pyrimidinone formation was followed
by Suzuki coupling to provide analog 21.
OMe
O
N
O
D
X
C N
N
A
B
Cl
Y
Finally, thiazole derivative 25 was synthesized as
detailed in Scheme 4. Reaction of methyl 4-chloroben-
zenecarbodithioate (22) with cyanamide and potassium
methoxide in methanol yielded compound 23. Treat-
ment of compound 23 with methyl-mercaptoacetate
and triethylamine afforded thiazole 24 which was then
converted to pyrimidinone 25.
Compound
X
Y
MCH R1 pIC50
7c
16
21
25
S
CH
CH
CH
N
9.3
6.9
8.2
8.5
O
CH@CH
S
The difference in the MCH R1 antagonist activities of
the analogs was striking, with pIC50’s ranging from a
high of 9.3 for 7c to a low of 6.9 for furan 16 (Table
2). Molecular modeling was employed to identify key
differences between the analogs that might help to ex-
plain the differences in potency. Figure 1 shows the rela-
tionship of the benzo, thieno, and furan derivatives with
the C and D rings overlaid (the right-hand alkoxyamine
fragment has been omitted for clarity).10
OMe
O
N
b
O
COCl
NO2
a
N
H
Cl
Figure 1. B-Ring comparison by molecular modeling. Red = furano
(16); green = thieno (7c); yellow = thiazolo (25); blue = benzo (21).
X
Cl
18 X=NO2
17
19 X=NH2
The ground state conformations reveal a marked differ-
ence in the orientation of the A-rings as dictated by the
corresponding B-rings (Fig. 1). Of particular note is the
central region in space occupied by the thiophene deriv-
ative 7c relative to the benzo and furo derivatives 21 and
16, respectively. This analysis implies that this orienta-
tion of 7c is optimal, and that the more ‘northerly’ ori-
entation of the A-ring as dictated by the furan derivative
is especially deleterious to MCH R1 activity.
c
OMe
O
OMe
N
O
O
d
N
O
N
N
N
N
Cl
Cl
21
20
Scheme 3. Reagents and conditions: (a) 3-methoxy-4-(2-pyrrolidin-1-
ylethoxy)aniline, Et3N, CH2Cl2, 25 ꢁC, 14 h, 69%; (b) SnCl2 H2O;
EtOH, 78 ꢁC, 4 h, 97%; (c) formic acid, 100 ꢁC, 3 h, 91%; (d) (4-
ClPh)B(OH)2, 2-(di-tert-butylphosphino)biphenyl, Pd(OAc)2, KF,
1 M Na2CO3, THF, 70 ꢁC, 3 h, 60%.
We next turned our attention to determining if the
amide-like carbonyl of the pyrimidinone-containing

4726
D. L. Hertzog et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4723–4727
0
Br
S
O2N
Br
a
Cl
OHC
27
26
Vehicle (n = 8)
-4
b, c
Sibutramine (3 mg/kg, n = 8)
Compound 7c (0.3 mg/kg, n = 8)
Compound 7c (3 mg/kg, n = 8)
Compound 7c (15 mg/kg, n = 8)
OMe
O
N
S
-8
Cl
28
Scheme 5. Reagents and conditions: (a) (4-chlorophenyl)methanethiol,
K2CO3, DMF, 60 ꢁC, 14 h then reflux, 24 h, 62%; (b) 1-(2-{[2-
(methyloxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]oxy}-
acetyl)pyrrolidine,16 Pd(PPh3)3, satd NaHCO3, DME, 80 ꢁC, 45 min,
40%; (c) AlH3, THF, 25 ꢁC, 1 h, 50%.
-12
-16
Figure 2. Effect of compound 7c (GW803430) at 0.3, 3, and 15 mg/kg
(orally, qd, n = 8 for each dosing group) on body weight loss in high fat
diet-induced obese AKR/J mice. Weight loss is expressed as percentage
weight change from pretreatment value for each treatment group
(average pretreatment body weight value was 45.9 0.7 g). Values are
means SEM, n = number of mice per group.
-
O
+
Cl
Cl
S
a
S
N
N
N
N
30
29
b
OMe
O
Cl
Cl
receptors, ion channels, and enzymes. The efficacy of
compound 7c in inducing weight loss was evaluated in
diet-induced obese AKR/J mice on a high fat diet
(58% kcal of fat, Research Diets #D12331).
S
S
N
N
Cl
c, d
N
N
N
32
31
Scheme 6. Reagents and conditions: (a) 30% H2O2, AcOH, 60 ꢁC, 2 h;
(b) POCl3, reflux, 1 h, 31% (two steps); (c) 1-({[4-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)phenyl]oxy}acetyl)pyrrolidine,16 (1,4-bis(di-
phenylphosphino)butane)palladium dichloride, CsF, DME, reflux,
12 h, 41%; (d) AlH3, THF, 25 ꢁC, 1 h, 24%.
As shown in Figure 2, during a 12-day treatment, oral
administration of compound 7c at 0.3, 3, and 15 mg/
kg once daily caused a sustained dose-dependent weight
loss of À6.2%, À12.1%, and À13.1%, respectively, rela-
tive to vehicle controls.17 In addition to compound 7c,
the marketed weight loss agent sibutramine (Meridiaꢂ)
was dosed at 3 mg/kg, resulting in a weight loss of
À1.9% relative to control animals.
analogs was necessary for MCH R1 antagonist activity.
Thus, we prepared analogs 28 and 32 as detailed in
Schemes 5 and 6. Benzothiophene 28 was prepared from
4-bromo-2-nitrobenzaldehyde 26 using the procedure of
Patel and co-workers.11 Suzuki coupling was followed
by amide reduction to provide analog 28. Thienopyr-
azine 32 was prepared through selective N-oxidation
of compound 29 followed by chlorination.12 Subsequent
Suzuki coupling and amide reduction provided the de-
sired analog 32 (Scheme 6).
In summary, a study of the structure–activity relation-
ships of a series of pyrimidinone-containing MCH R1
antagonists was conducted and critical structural
elements for MCH R1 activity were identified. One of
the compounds was shown to be active in an animal
model of obesity.
References and notes
Interestingly, analogs 28 and 32 demonstrated no signif-
icant MCH R1 activity. Thus, the carbonyl group of the
pyrimidinone appears to be critical for activity in this
series. We speculate that the carbonyl oxygen is acting
as a critical H-bond acceptor within this series of
MCH R1 antagonists. This result is consistent with
computational studies performed on related analogs.13
1. Qu, D.; Ludwig, D. S.; Gammeltoft, S.; Piper, M.;
Pelleymounter, M. A.; Cullen, M. J.; Mathes, W. F.;
Przypek, J.; Kanarek, R.; Maratos-Flier, E. Nature 1996,
380, 243.
2. Shimada, M.; Tritos, D.; Aitken, A.; Donella-Deana, A.;
Hemmings, B. A.; Parker, P. J. Nature 1998, 396, 670.
3. (a) Chen, Y.; Hu, C.; Hsu, C. K.; Zhang, Q.; Bi, C.;
Asnicar, M.; Hsiung, H. M.; Fox, N.; Slieker, L. J.; Yang,
D. D.; Heiman, M. L.; Shi, Y. Endocrinology 2002, 143,
2469; (b) Marsh, D. J.; Weingarth, D. T.; Novi, D. E.;
Chen, H. Y.; Trumbauer, M. E.; Chen, A. S.; Guan, X.
M.; Jiang, M. M.; Feng, Y.; Camacho, R. E.; Shen, Z.;
Frazier, E. G.; Yu, H.; Metzger, J. M.; Kuca, S. J.;
Shearman, L. P.; Gopal-Truter, S.; Macneil, D. J.; Strack,
A. M.; MacIntyre, D. E.; Van der Ploeg, L. H.; Qian, S.
Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 3240.
We sought to establish the utility of these MCH R1
antagonists in an animal model of obesity. The maleate
salt of compound 7c (GW803430) was deemed to be a
suitable compound for such a study given its good phar-
macokinetic properties (bioavailability = 31%, t1/2
=
11 h) and brain penetration (6:1 brain:plasma concen-
tration) in mice.14,15 Importantly, 7c was found to be
selective (>100·) over a battery of G-protein coupled

D. L. Hertzog et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4723–4727
4727
4. Several patents describing MCH R1 patents have been
published. For reviews on the subject, please see: (a)
Dyke, H. J.; Ray, N. C. Expert Opin. Ther. Patents
2005, 15, 1303; (b) Kowalski, T. J.; McBriar, M. D.
Expert Opin. Invest. Drugs 2004, 13, 1113; (c) Browning,
A. Expert Opin. Ther. Patents 2004, 14, 313; (d) Collins,
C. A.; Kym, P. R. Curr. Opin. Invest. Drugs 2003, 4,
386.
The atoms of the pyrimidinone ring were superimposed
to demonstrate the variation in the position of the
4-chlorophenyl substituent on the fused heterocyclic ring.
11. Patel, M. V.; Rohde, J. J.; Gracias, V.; Kolasa, T.
Tetrahedron Lett. 2003, 44, 6665.
12. Kruse, C. G.; Timmermans, P. B. M. W. M.; van der
Laken, C.; van der Gen, A. Recl. Trav. Chim. 1978, 97,
151.
5. (a) Witty, D. R.; Bateson, J.; Hervieu, G. J.; Jeffrey, P.;
Johnson, C. N.; Muir, A. I.; O’Hanlon, P. J.; Stemp, G.;
Stevens, A. J.; Thewlis, K.; Winborn, K. Y. Bioorg. Med.
Chem. Lett., in press; (b) Witty, D. R.; Bateson, J.;
Hervieu, G. J.; Al-Barazanji, K.; Jeffrey, P.; Hamprecht,
D.; Haynes, A.; Johnson, C. N.; Muir, A. I.; O’Hanlon,
P. J.; Stemp, G.; Stevens, A. J.; Thewlis, K.; Winborn, K.
Y. Bioorg. Med. Chem. Lett., in press.
6. Prepared through Jones oxidation of the corresponding
aldehyde found in Sone, C.; Matsuki, Y. Bull. Chem. Soc.
Japan 1963, 36, 618.
7. Gupton, J. T.; Miller, J. F.; Bryant, R. D.; Maloney, P. R.;
Foster, B. S. Tetrahedron 1987, 43, 1747.
13. Tavares, F. X.; Al-Barazanji, K. A.; Bigham, E. C.;
Bishop, M. J.; Britt, C. S.; Carlton, D. L.; Feldman,
P. L.; Goetz, A. S.; Grizzle, M. K.; Guo, Y. C.;
Handlon, A. L.; Hertzog, D. L.; Ignar, D. M.; Lang,
D. G.; Ott, R. J.; Peat, A. J.; Zhou, H-Q. J. Med.
Chem., in press.
14. Handlon, A. L.; Al-Barazanji, K.; Barvian, K. K.;
Bigham, E. C.; Carlton, D. L.; Carpenter, A. J.; Cooper,
J. P.; Daniels, A. J.; Garrison, D. T.; Goetz, A. S.; Green,
G. M.; Grizzle, M. K.; Guo, Y. C.; Hertzog, D. L.;
Hyman, C. E.; Ignar, D. M.; Peckham, G. E.; Speake, J.
D.; Britt, C.; Swain, W. R. Abstracts of Papers. In 228th
National Meeting of the American Chemical Society;
American Chemical Society: Washington, DC, 2004,
p. 193.
8. The compounds were assayed for MCH R1 functional
antagonist activity as described in WO 2004/092181 A1
(corrected version), pp 215–216. CHO cells expressing an
elkgal4-luc+ reporter gene (host) were transfected with
human MCH R1. The ability of the antagonists to inhibit
an EC80 response of MCH was assessed via a TopCount
microplate scintillation counter (Packard) and the speci-
ficity of the MCH R1 response was determined by
measuring the ability of the antagonists to inhibit an
EC80 thrombin response in the host cells. All compounds
were assayed with n P 4.
15. The maleate salts of compound 7c and related analogs
were often made to provide easily handled solids that were
not hygroscopic.
16. 1-({[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
oxy}acetyl)pyrrolidine has the following structure:
O
O
N
O
B
O
9. Redman, A. M.; Dumas, J.; Scott, W. J. Org. Lett. 2000, 2,
2061.
17. The weight loss achieved with GW803430 (compound 7c)
was due entirely to fat mass loss as determined by dual-
energy X-ray absorptiometry (DEXA) scanning. See Al-
Barazanji, K.; Grizzle, M.; Britt, C.; Lancaster, M.;
Daniels, A.; Ignar, D.; Cooper, J; Hertzog, D. Obesity
Res. 2004, 12, 56-OR.
10. Molecular models of the structures in Figure 1 were
created using the Maestro Version 7.5 interface from
Schro¨dinger, LLC. In Maestro, conformation searches
and energy minimizations were carried out with the
MacroModel application using the OPLS-2005 force field.