Spiroindane based amides as potent and selective MC4R agonists for the treatment of obesity

Article abstract of DOI:10.1016/j.bmcl.2010.06.062

We report a series of potent and selective MC4R agonists based on spiroindane amide privileged structures for potential treatments of obesity. Among the synthetic methods used, Method C allows rapid synthesis of the analogs. The series of compounds can afford high potency on MC4R as well as good rodent pharmacokinetic profiles. Compound 1r (MK-0489) demonstrates MC4R mediated reduction of food intake and body weight in mouse models. Compound 1r is efficacious in 14-day diet-induced obese (DIO) rat models.

Full text of DOI:10.1016/j.bmcl.2010.06.062

Bioorganic & Medicinal Chemistry Letters 20 (2010) 4399–4405
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Spiroindane based amides as potent and selective MC4R agonists
for the treatment of obesity
a
a
a
a
a
Shuwen He a, , Zhixiong Ye , Peter H. Dobbelaar , Iyassu K. Sebhat , Liangqin Guo , Jian Liu ,
Tianying Jian a, Yingjie Lai a, Christopher L. Franklin a, Raman K. Bakshi a, James P. Dellureficio a,
Qingmei Hong a, David H. Weinberg b, Tanya MacNeil b, Rui Tang b, Alison M. Strack c,
Constantin Tamvakopoulos d, Qianping Peng d, Randy R. Miller d, Ralph A. Stearns d, Howard Y. Chen b,
Airu S. Chen b, Tung M. Fong b, Matthew J. Wyvratt Jr. a, Ravi P. Nargund a
*
a Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
b Department of Metabolic Disorders, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
c Department of Pharmacology, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
d Department of Drug Metabolism, Merck Research Laboratories, 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:
We report a series of potent and selective MC4R agonists based on spiroindane amide privileged struc-
tures for potential treatments of obesity. Among the synthetic methods used, Method C allows rapid syn-
thesis of the analogs. The series of compounds can afford high potency on MC4R as well as good rodent
pharmacokinetic profiles. Compound 1r (MK-0489) demonstrates MC4R mediated reduction of food
intake and body weight in mouse models. Compound 1r is efficacious in 14-day diet-induced obese
(DIO) rat models.
Received 1 May 2010
Revised 5 June 2010
Accepted 10 June 2010
Available online 15 June 2010
Keywords:
Spiroindane
Ó 2010 Elsevier Ltd. All rights reserved.
Amide
Privileged structure
Melanocortin subtype-4 receptor
MC4R
Agonist
MK-0489
Obesity
Obesity has become a major health problem throughout the
world, especially in urbanized societies. The associated morbidi-
ties, such as type 2 diabetes, cardiovascular diseases, hypertension,
and certain types of cancers, further exacerbate the problem.1
Finally, the World Health Organization (WHO) officially declared
obesity a disease in 1998.2 This means that obesity is no longer
considered as a cosmetic issue, but rather a disease condition
requiring medical interventions. The drugs currently available to
patients suffer from variable efficacy and undesirable side effects.
Therefore, there are significant unmet medical needs for the treat-
ment of obesity.3
The melanocortin receptors with five subtypes (MC1R–MC5R)
are a family of seven-transmembrane G-protein coupled receptors
(GPCR’s). The endogenous peptides derived from tissue-specific
post-translational processing of proopiomelanocortin (POMC)
interact with the melanocortin receptors to regulate a wide range
of biological effects, including feeding behavior and body weight
homeostasis, skin pigmentation, steroid production, sexual behav-
iors, and exocrine gland secretion.4
The melanocortin subtype-4 receptor (MC4R) is primarily ex-
pressed in the brain. The evidence on its involvement in energy
balance and feeding behaviors is compelling. In human and mice,
loss-of-function mutations of MC4R genes are associated with
hyperphagia, obesity and metabolic defects.5 Some studies suggest
that MC4R is also involved in regulating reproductive function.6
With these strong validations, MC4R has emerged as an attractive
target against obesity as well as sexual dysfunction.
There have been intense efforts from our laboratories and
other research groups to identify selective small molecule
MC4R agonists.7,8 Recently, we disclosed spiroindane based acet-
yl amide compounds 1r and 1s (Fig. 1).7h,9 1r (also known as
MK-0489) is a potent and selective MC4R agonist with excellent
pharmacokinetics profiles in pre-clinical species. It shows excel-
lent pro-erectile activity in a mouse model. In this letter, we will
discuss our continued explorations in this spiroindane amide
privileged structure series, focusing on obesity as a possible
indication.
* Corresponding author. Tel.: +1 732 594 0881; fax: +1 732 594 3007.
E-mail address: shuwen_he@merck.com (S. He).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.06.062

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S. He et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4399–4405
Table 1
In vitro activities of 4r and 4s compared with 1r and 1sa
N
N
Human MC4R
binding IC50
(nM)
Human MC4R functional Human MC1bR
F
F
EC50 (nM) (% activation)
functional EC50 (nM) (%
O
O
activation)
N
N
1r 13
4.6 (109%)
3.3 (90%)
2.1 (112%)
4.3 (83%)
1020 (25%)
260 (43%)
494 (35%)
270 (41%)
1s
4r
4s
4.5
8.5
2.5
F
F
Cl
Cl
aData are averages of at least three repeated measurements
NHAc
1r (MK-0489)
NHAc
1s
Table 2
Rat pharmacokinetic data for 4ra
Figure 1. Structures of MK-0489 and its diastereomer 1s.
PK parameter
Rata
F (%)
22
9.1
10.4
15.1
0.83
Cl (mL minÀ1 kgÀ1
)
Initially, we prepared 4r and 4s, N-methyl analogs of 1r and 1s,
from known 2r and 2s (Scheme 1).7h Both 4r and 4s maintained the
potency on MC4R in the binding and functional assays (Table 1).10
They have comparable selectivity against MC1bR, which is an iso-
form of MC1R involved in regulating skin and hair color. Agonism
of MC1bR can lead to undesirable darkness of skin.11 Furthermore,
we were encouraged to find that 4r had good pharmacokinetic pro-
files in rat, with a half life of 15.1 h and good oral bioavailability
(22%) (Table 2).
Vdss (L kgÀ1
t1/2 (h)
AUCn (
)
lM h/mpk)
a
Compound dosed in Sprague–Dawley rats
solution in EtOH/PEG400/water
as
a
(10:40:50) at 1 mg/kg, iv and 4 mg/kg, po.
To improve the potency on MC4R, we further explored a series
with reverse amide privileged structures (Fig. 2). The first few ana-
logs in this series were prepared from racemic acid 7, available
from the selective chlorination of known acid 6,7h exemplified by
the preparation of di-methyl amide analogs (Method A, Scheme
2). The racemic amide 8 was resolved by chiral HPLC to give enan-
tiomers 8r and 8s. Each enantiomer was then coupled with the acid
5 to give the analogs 9r and 9s.12 With Method A, each privileged
structure required a chiral resolution in order to prepare a pair of
final analogs.
The reverse amide analog 9s had subnanomolar activity on
MC4R and good selectivity against MC1bR, while its diasteromer
9r was much less potent on MC4R (Table 3). In contrast, in the ori-
ginal acetyl amide series, 1r and 4r were as potent as their corre-
sponding diastereomers 1s and 4s (Table 1).
N
N
F
F
O
O
N
N
F
F
Cl
Cl
O
N
NH
O
R1
R2
Figure 2. Reverse amide design.
Table 3
In vitro activities of 9r and 9sa
To avoid resolving each privileged structure, we synthesized the
enantiomeric pure acids 7r and 7s (Scheme 3). The corresponding
racemic methyl ester 10 was resolved by chiral HPLC. Each enanti-
omerically pure ester was then hydrolyzed to provide the acids 7r
and 7s. To establish their stereochemistry, we correlated the acid
with the acetyl amide, whose stereochemistry was determined
Human MC4R
binding IC50
(nM)
Human MC4R functional Human MC1bR
EC50 (nM) (% activation)
functional EC50 (nM) (%
activation)
9r 59
9s 0.71
53 (80%)
0.87 (108%)
5000 (17%)
255 (92%)
a
Data are averages of at least three repeated measurements.
CO2t-Bu
N
CO2t-Bu
N
N
F
O
a
b, c
Cl
Cl
N
NHAc
N
O
F
2r
or
3r
or
4r
Cl
or
2s
3s
4s
N
O
N
O
HO
F
5
F
Scheme 1. Reagents: (a) KHMDS, MeI, THF; (b) 4 M HCl in dioxane; (c) acid 5, HATU, HOAt, NMM, CH2Cl2.

S. He et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4399–4405
4401
CO2t-Bu
N
CO2t-Bu
N
CO2t-Bu
N
a
b
Cl
Cl
O
CO2H
CO2H
N
6
7
8
racemic
racemic
racemic
CO2t-Bu
N
CO2t-Bu
N
c
Cl
Cl
+
O
O
N
N
8r
fast eluting enantiomer
8s
slow eluting enantiomer
N
N
F
F
O
O
N
N
F
F
Cl
Cl
O
O
N
N
9r
9s
Scheme 2. Preparation of amide analogs: Method A (exemplified by the preparation of 9r and 9s). Reagents and conditions: (a) N-chlorosuccinimide, DMF, 50 °C; (b) (COCl)2,
DMF (cat.), CH2Cl2, 0 °C; (c) NHMe2 (2 M in THF), 0 °C to rt; (d) chiral AD column, EtOH–heptane; (d) 4 M HCl in dioxane; (e) acid 5, HATU, HOAt, NMM, CH2Cl2.
CO2t-Bu
N
CO2t-Bu
N
a
b
Cl
Cl
CO2H
CO2Me
7
10
racemic
racemic
CO2t-Bu
N
CO2t-Bu
N
CO2t-Bu
N
+
Cl
Cl
Cl
CO2H
CO2Me
CO2Me
7s
fast eluting enantiomer
slow eluting enantiomer
10r
10s
CO2t-Bu
N
CO2t-Bu
N
CO2t-Bu
N
c, d
e, f
SiMe3
O
O
Cl
Cl
Cl
N
H
O
N
H
CO2H
7r
2r
Scheme 3. Preparation of enantiomerically pure acid 7r and 7s and determination of their configurations. Reagents and conditions: (a) TMSCHN2, MeOH; (b) chiral AD
column, EtOH–heptane; (c) DPPA, Et3N, toluene, reflux; (d) HOCH2CH2SiMe3, reflux; (e) TBAF, THF, 50 °C; (f) CH3COCl, Et3N, CH2Cl2.

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S. He et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4399–4405
Table 4
Potency of secondary amide analogs on human MC4R and MC1bR
Compound
N
F
O
hMC4R agonism EC50
nM (% activation)a
,
hMC1bR agonism EC50
nM (% activation)a
,
NHR
Preparation method
hMC4R binding IC50, nMa
N
F
Cl
O
HN
R
13r
13s
14r
14s
A
A
A
A
47
12 (86%)
1375 (38%)
323 (60%)
1417 (26%)
295 (50%)
NH
2.6
53
0.91 (94%)
32 (96%)
NH
NH
NH
3.1
1.4 (100%)
15r
15s
16s
17s
18s
19s
B
B
C
C
C
C
55
28 (95%)
0.80 (95%)
2.9 (92%)
9.9 (76%)
27(92%)
1115 (20%)
243 (50%)
435 (45%)
1033 (47%)
2050 (45%)
935(29%)
NH
NH
NH
NH
NH
NH
2.2
5.9
12
6.6
12
42 (79%)
F
F
20s
21r
21s
22s
C
B
B
C
2.6
93
1.1 (84%)
307 (78%)
4.2 (89%)
1.3 (100%)
260 (48%)
NDb (5%)
838 (30%)
83 (56%)
NH
NH
NH
NH
F
F
F
F
5.4
2.6
F
OH
O
23s
24s
C
C
2.5
3.9
2.3 (92%)
1.9 (89%)
260 (74%)
218 (53%)
NH
NH
OH
a
The reported data are the average of at least three repeated experiments.
Not determined.
b
previously.7h Curtis rearrangement of acid 7r gave an isocyanate
intermediate, which was trapped with trimethylsilyl ethanol. The
Teoc protecting group was removed to give the amine, which
was acylated to give the acetyl amide. This sample had a chiral
HPLC retention time identical to that of the enantiomerically pure
amide 2r, but different from that of amide 2s. Therefore, 7r and 2r
had the same configuration, so did 7s and 2s. Through this effort,
enantiomerically pure acids 7r and 7s were obtained with the ste-
reochemistry firmly established.
To determine the stereochemistry of the analogs prepared by
Method A (Scheme 2), we repeated the synthesis of the amide priv-
ileged structures from the enantiomerically pure 7r and/or 7s. By
comparing the amides with the amides previously prepared from
racemic acid by chiral HPLC, we established the stereochemistry
of all analogs prepared by Method A.
From 7r and 7s, we prepared more analogs according to
Method B (Scheme 4). This method required isolation of the
amide privileged structure prior to coupling with acid 5. The

S. He et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4399–4405
4403
N
CO2t-Bu
N
CO2t-Bu
N
F
O
N
a, b
c, d
F
Cl
Cl
O
R1
Cl
CO2H
O
N
R2
R1
7r
or
N
R2
amide privileged structure
7s
Scheme 4. Preparation of amide analogs: Method B. Reagents and conditions: (a) (COCl)2, DMF (cat.), CH2Cl2, 0 °C; (b) NHR1R2, 0 °C to rt; (c) 4 M HCl in dioxane; (d) acid 5,
HATU, HOAt, NMM, CH2Cl2.
Table 5
The potency of tertiary amide analogs on human MC4R and MC1bR
Compound
N
F
O
hMC4R agonism EC50
,
hMC1bR agonism EC50
nM (% activation)a
,
NR1R2
Synthetic method
hMC4R binding IC50, nMa
N
nM (% activation)a
F
Cl
O
N
R1
R2
9r
A
A
C
59
53 (80%)
5000 (17%)
255 (92%)
355 (69%)
N
N
N
9s
0.71
2.1
0.87 (108%)
1.6 (103%)
25s
26s
27s
C
C
2.6
1.1
1.7(81%)
168 (67%)
238 (72%)
N
N
0.59 (88%)
F
F
N
28s
C
1.8
4.3 (78%)
430 (46%)
29s
30s
31s
N
N
N
O
O
C
C
C
0.85
1.6
0.38 (94%)
0.76(96%)
1.0 (73%)
84 (66%)
69 (72%)
223 (60%)
1.8
F
32s
33s
C
C
1.6
1.4
1.1 (87%)
122 (69%)
203 (68%)
N
N
F
0.98 (106%)
F
F
34s
C
2.0
3.8 (96%)
285 (54%)
N
N
N
N
N
OH
OH
35s
36s
37s
38s
C
C
C
C
0.53
0.89
1.4
0.25 (98%)
0.37 (88%)
0.69 (111%)
1.2 (112%)
33 (71%)
29 (93%)
103 (67%)
102 (71%)
O
O
2.3
a
The reported data are the average of at least three repeated experiments.

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S. He et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4399–4405
N
N
F
F
CO2t-Bu
N
H2
N
O
Cl
O
N
N
a
b
c
F
F
Cl
Cl
Cl
Cl
CO2H
CO2H
O
O
N
N
R1
N
O
N
R2
7s
11s
N
12s
Scheme 5. Preparation of amides analog: Method C. Reagents: (a) 4 M HCl in dioxane; (b) acid 5, HATU, HOAt, NMM, DMF; (c) amine HNR1R2.
(Table 3), each analog with S configuration is more potent than
Table 6
Pharmacokinetic data for 9s and 28sa
its R diastereomer on MC4R. In the secondary amide S configura-
tion series (Table 4), bulkier amides (tert-butyl and benzyl in 17s
and 19s) reduce MC4R potency while incorporation of oxygen
atom (23s and 24s) tends to restore the potency. The tertiary
amide analogs (Table 5) are generally more potent that the second-
ary amide analogs on MC4R. Small alkyl amides offer good potency
(9s, 25s, 26s, and 27s). For the pyrrolidine amide analogs, mono
fluoro (32s) has indistinguishable MC4R potency compared with
the parent (31s) while incorporation of di-fluoro (34s) has reduced
potency. Substitution by an oxygen atom is well tolerated (e.g., 29s
and 30s). Two pyrrolidinol analogs (35s and 36s) are equally po-
tent. Methylation of the alcohol slightly reduces the potency (37s
and 38s). Many analogs are extremely potent on MC4R with subn-
anomolar potency. However, their activities on MC1bR also in-
crease although most of them maintain an EC50 ratio of v.s.
MC4R greater than 100.
PK parameter
9s
28s
F (%)
24
29
21.8
8.88
7.3
Cl (mL minÀ1 kgÀ1
)
17.2
Vdss (L kgÀ1
t1/2 (h)
)
6.95
5.14
0.39
AUCn (
lM h/mpk)
0.35
aCompound dosed in Sprague–Dawley rats as a solution in EtOH/
PEG400/water (10:40:50) at 1 mg/kg, iv and 4 mg/kg, po.
data of the analogs made by this method will be summarized in
Tables 4 and 5.
Finally, we developed a unique and convenient method to pre-
pare a library of analogs efficiently (Scheme 5, Method C). In con-
trast to Methods A and B, Method C was a one-pot procedure from
the acid to the final analog without isolation of any intermediate.13
Routine de-Boc with HCl gave the corresponding HCl salt 11s,
which was then treated with acid 5, HOAt (3 equiv) and HATU.
Flanked by the gem-dimethyl groups, the acid group in 11s was
much more hindered sterically than the acid group in compound
5. With no dimerization of 11s observed, piperidine nitrogen in
11s was acylated by acid 5 to give intermediate 12s, where the
gem-dimethyl acid group was terminated by formation of HOAt es-
ter. This activated ester, upon treatment of an amine, formed the
amide bond to give the analog.13 Using Method C, we prepared
the library rapidly. The analogs are listed together with others pre-
pared by Methods A and B.
Two additional compounds (9s and 28s) were also tested in rat
PK. Both compounds had good oral bioavailability and reasonable
half life in rat (Table 6).
Finally, 1r (MK-0489) was evaluated in rodent obesity efficacy
models. It was first tested in wild type (WT) v.s. MC4R/3R knock-
out (KO) mouse for food intake and body weight change (Fig. 3).14
Compared with vehicle, after oral dosing of 1r at 10 mg/kg, signif-
icant reduction of food intake and body weight was observed in
WT mice but not in KO mice. Since 1r was much less active on
MC3R than MC4R,7h,15 we concluded that the observed efficacy
was mediated through MC4R. Compound 1r was also tested in a
14-day diet-induced obese rat model ( Fig. 4). In this study, 1r
was dosed orally to rats at 2, 6, 20 mpk twice a day. Control 1
(10 mpk, twice a day)16 and control 2 (dexfenfluramine, 3 mpk
once a day) were dosed orally as positive controls. The body weight
of the rat was recorded daily. Compound 1r dosed at 6 mpk had
Tables 4 and 5 summarize MC4R and MC1bR activities of the
analogs with this reverse amide design. Table 4 includes the com-
pounds with secondary amides, while Table 5 covers the tertiary
amides. Consistent with the data for 9s and 9r described earlier
Food intake
Body weight
A
B
-
WT veh
WT 1sr, 10mpk
KO veh
1sr
KO , 10mpk
-
WT veh
5
4
3
2
1
0
-
1.5
1
p=0.002 (15%)
-
-
-
WT 1sr, 10mpk
-
KO veh
p=0.0005
-
KO 1sr, 10mpk
0.5
0
p=0.000 (34%)
-0.5
-1
4-hr FI
18-hr FI
Figure 3. Food intake (FI) and body weight (BW) in wild type mouse and MC4R/3R knock-out mouse after oral dosing of 1r.

S. He et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4399–4405
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10 11 12 13
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Figure 4. Body weight effect of orally dosed 1r in diet-induced obese rats.
efficacy similar to control 1 dosed at 10 mpk. When dosed at
20 mpk twice a day, 1r afforded efficacy comparable to that of con-
trol 2 dosed at 3 mpk once a day.
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r or s in the compound number
designates the R or S configuration at the stereogenic carbon of the spiroindane.
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T.; Kalyani, R. N.; Tang, R.; Van der Ploeg, L. H. T.; Weinberg, D. H. J. Med. Chem.
2001, 44, 3665; (c) Bednarek, M. A.; Siva, M. V.; Arison, B.; MacNeil, T.; Kalyani,
R. N.; Huang, R.-R. C.; Weinberg, D. H. Peptides 1999, 20, 401.
11. Tan, C. P.; McKee, K. K.; Weinberg, D. H.; MacNeil, T.; Palyha, O. C.; Feighner, S.
D.; Hreniuk, D. L.; Van Der Ploeg, L. H. T.; MacNeil, D. J.; Howard, A. D. FEBS Lett.
1999, 451, 137.
12. We were able to establish the R/S configuration analog 9r and 9s (see
discussion later in the text).
13. Experimental details for Method C exemplified by the preparation of 28s: acid
7s (60 mg, 0.143 mmol) was dissolved in CH2Cl2 (0.5 mL) and treated with 4 M
HCl in dioxane (2 mL) at rt. Upon completion of de-Boc, the mixture was
concentrated in vacuo. The residue was dissolved in DMF (2 mL) and treated
In summary, we have described our discovery of potent and
selective MC4R agonists in the spiroindane amide privileged struc-
ture series. Many potent analogs with S stereochemistry on the
spiroindane possess subnanomolar in vitro potency on MC4R. Sev-
eral compounds also show good rodent pharmacokinetics profile.
Furthermore, 1r (MK-0489) demonstrates MC4R mediated efficacy
in an acute mouse model of obesity as well as good efficacy in a 14-
day DIO rat model. Further interrogation of the SAR of this series is
the subject of the following communication.
with N-methylmorpholine (NMM) (94
(58 mg, 0.429 mmol), HATU (163 mg, 0.429 mmol) and acid
l
L, 0.858 mmol), followed by HOAt
References and notes
5
(49 mg,
0.172 mmol). The mixture was stirred overnight at rt. The mixture was then
treated with 3,3-difluoroazetidine HCl salt (185 mg, 1.43 mmol) and NMM
(314 lL, 2.86 mmol) at rt. Upon completion of reaction, the mixture was
1. Haslam, D. W.; James, W. P. Lancet 2005, 366, 1197.
2. Obesity: Preventing and Managing the Global Epidemic, Report of a WHO
Consultation, World Health Organization, Geneva, 2004.
purified by reverse HPLC to give the analog 28s.
3. Bays, H. E. Obes. Res. 2004, 12, 1197.
14. For a discussion of MC4R/3R knock out mouse, see: Chen, A. S.; Marsh, D. J.;
Trumbauer, M. E.; Frazier, E. G.; Guan, X.-M.; Yu, H.; Rosenblum, C. I.; Vongs, A.;
Feng, Y.; Cao, L.; Metzger, J. M.; Strack, A. M.; Camacho, R. E.; Mellin, T. N.;
Nunes, C. N.; Min, W.; Fisher, J.; Gopal-Truter, S.; MacIntyre, D. E.; Chen, H. Y.;
Van der Ploeg, L. H. T. Nat. Genet. 2000, 26, 97.
15. Compound 1r has in vitro functional activity of 22 nM (EC50) on mouse MC4R
and 1.7 lM (EC50) on mouse MC3R.
16. Control 1 was discovered previously in our laboratories. Ujjainwalla, F; Sings,
4. (a) Cone, R. D. Endocr. Rev. 2006, 27, 736; (b) Gantz, I.; Fong, T. M. Am. J. Physiol.
Endocrinol. Metab. 2003, 284, E468; (c) Yang, Y. K.; Harmon, C. M. Obes. Rev.
2003, 4, 239.
5. (a) Huszar, D.; Lynch, C. A.; Fairchild-Huntress, V.; Dunmore, J. H.; Fang, Q.;
Berkemeier, L. R.; Gu, W.; Kesterson, R. A.; Boston, B. A.; Cone, R. D.; Smith, F. J.;
Campfield, L. A.; Burn, P.; Lee, F. Cell 1997, 88, 131; (b) Vaisse, C.; Clement, K.;
Guy-Grand, B.; Froguel, P. Nat. Genet. 1998, 20, 113; (c) Yeo, G. S.; Farooqi, I. S.;
Aminian, S.; Halsall, D. J.; Stanhope, R. G.; O’Rahilly, S. Nat. Genet. 1998, 20, 111.
6. (a) Van der Ploeg, L. H. T.; Martin, W. J.; Howard, A. D.; Nargund, R. P.; Austin, C.
P.; Guan, X.; Drisko, J.; Cashen, D.; Sebhat, I.; Patchett, A. A.; Figueroa, D. J.;
DiLella, A. G.; Connolly, B. M.; Weinberg, D. H.; Tan, C. P.; Palyha, O. C.; Pong, S.-
S.; MacNeil, T.; Rosenblum, C.; Vongs, A.; Tang, R.; Yu, H.; Sailer, A. W.; Fong, T.
M.; Huang, C.; Tota, M. R.; Chang, R. S.; Stearns, R.; Tamvakopoulos, C.; Christ,
G.; Drazen, D. L.; Spar, B. D.; Nelson, R. J.; MacIntyre, D. E. Proc. Natl. Acad. Sci.
U.S.A. 2002, 99, 11381; (b) Hadley, M. E. Peptides 2005, 26, 1687.
H. L. unpublished results.
F
F
N
O
N
7. (a) Nargund, R. P.; Strack, A. M.; Fong, T. M. J. Med. Chem. 2006, 49, 4035; (b)
Ujjainwalla, F.; Sebhat, I. K. Curr. Top. Med. Chem. 2007, 7, 1068; (c) Sebhat, I. K.;
Martin, W. J.; Ye, Z.; Barakat, K.; Mosley, R. T.; Johnston, D. B. R.; Bakshi, R.;
Palucki, B.; Weinberg, D. H.; MacNeil, T.; Kalyani, R. N.; Tang, R.; Stearns, R. A.;
Miller, R. R.; Tamvakopoulos, C.; Strack, A. M.; McGowan, E.; Cashen, D. E.;
Drisko, J. E.; Hom, G. J.; Howard, A. D.; MacIntyre, D. E.; van der Ploeg, L. H. T.;
Patchett, A. A.; Nargund, R. P. J. Med. Chem. 2002, 45, 4589; (d) Palucki, B. L.;
Park, M. K.; Nargund, R. P.; Ye, Z.; Sebhat, I. K.; Pollard, P. G.; Kalyani, R. N.;
Tang, R.; MacNeil, T.; Weinberg, D. H.; Vongs, A.; Rosenblum, C. I.; Doss, G. A.;
Miller, R. R.; Stearns, R. A.; Peng, Q.; Tamvakopoulos, C.; McGowan, E.; Martin,
W. J.; Metzger, J. M.; Shepherd, C. A.; Strack, A. M.; MacIntyre, D. E.; Van der
Ploeg, L. H. T.; Patchett, A. A. Bioorg. Med. Chem. Lett. 2005, 15, 171; (e)
Ujjainwalla, F.; Warner, D.; Snedden, C.; Grisson, R. D.; Walsh, T. F.; Wyvratt, M.
J.; Kalyani, R. N.; MacNeil, T.; Tang, R.; Weinberg, D. H.; van der Ploeg, L. H. T.;
O
N
H
Cl
control 1
hMC4R binding IC50 70 nM
agonism EC50 18 nM
(97% act.)