Diaryl piperidines as CB1 receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2009.11.075

The syntheses and SAR investigations of novel CB₁ receptor antagonists based on a 1,2-diaryl piperidine core have been described. Optimization of this core afforded a compound with robust in vivo potency by reducing food intake in a mouse DIO m

Full text of DOI:10.1016/j.bmcl.2009.11.075

Bioorganic & Medicinal Chemistry Letters 20 (2010) 1278–1283
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Diaryl piperidines as CB1 receptor antagonists
a
b
a
a
a
Jack D. Scott a, , Sarah W. Li , Hongwu Wang , Yan Xia , Charles L. Jayne , Michael W. Miller ,
Ruth A. Duffy c, George C. Boykow c, Timothy J. Kowalski c, Brian D. Spar c, Andrew W. Stamford a,
Samuel Chackalamannil a, Jean E. Lachowicz c, William J. Greenlee a
*
a Department of Medicinal Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
b Department of Structural Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
c Department of Metabolic Disorders, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The syntheses and SAR investigations of novel CB1 receptor antagonists based on a 1,2-diaryl piperidine
core have been described. Optimization of this core afforded a compound with robust in vivo potency by
reducing food intake in a mouse DIO model.
Received 25 September 2009
Revised 14 November 2009
Accepted 17 November 2009
Available online 20 November 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
CB1 Antagonist
CB1 Receptor
Cannabinoid CB1
Piperidine
Obesity
To date, two receptors in the cannabinoid system have been
recent reports of inverse antagonists based on a piperazine core10
and antagonists with a bicyclic lactam core.11
1
cloned, CB1 and CB2.2 Both of these receptors belong to the GPCR
superfamily. The CB1 receptor is expressed in the CNS and several
peripheral tissues while the CB2 receptor is expressed in the im-
mune system, gastrointestinal system and to a lesser extent in
the brain. Antagonists or inverse agonists of the CB1 receptor have
been shown to reduce food intake in both animals3 and in humans4
leading to a possible treatment for obesity. Rimonabant (1, Fig. 1),5
a potent and selective CB1 inverse agonist, has been shown in clin-
ical studies to reduce body weight and improve cardiovascular bio-
markers such as plasma lipid levels.4 Rimonabant was approved as
a treatment for obesity in the European Union in 2006; however, it
was removed from the market in 2008 due to psychiatric side-ef-
fects. Taranabant (2),6 which has an acyclic amide core, and oten-
abant (3)7 were both in phase III clinical trials when their
respective developments were discontinued. In spite of these re-
sults, there remains a significant motivation to identify novel CB1
receptor antagonists as it is unclear whether the observed side-ef-
fects are solely mechanism of action based.
Molecular modeling of rimonabant within the CB1 receptor has
provided significant information towards the understanding of the
inverse agonist-receptor interactions. The two aromatic substitu-
ents of rimonabant have been proposed to play an important role
with the interaction of an aromatic microdomain in the CB1 recep-
tor.12 It has also been reported that the carbonyl of rimonabant
acts as a hydrogen bond acceptor to the inactive state of the CB1
receptor leading to the observed inverse agonism.13 An in-house
pharmacophore model derived from eight reported CB1 antago-
nists or inverse agonists used these key domains and an additional
hydrophobic pocket to screen for CB1 antagonists.14
In-house screening of our compound inventory towards the
identification of CB1 antagonists indicated that compounds with
a fully saturated core could be viable leads for this program.15 Ini-
tial efforts focused on the preparation of a saturated cyclic core
substituted with two aryl groups. Based on literature precedent
for the preparation of 1,6-diarylpiperidin-2-ones16 that were ame-
nable to further elaboration at the 3-position, a piperidin-2-one
core structure was investigated (Fig. 2).
Most of the CB1 antagonists or inverse agonists reported in the
literature are based on a heteroaromatic core substituted with two
aromatic groups.8 Examples of CB1 modulators based on non-aro-
matic cores include taranabant, a series of diarylpyrazolines9 and
Initial SAR investigations were focused on optimal relative ste-
reochemistry of the core along with the chlorination pattern on the
two aromatic substituents. Friedel–Crafts acylation of 4-chloro-
benzene or 2,4-dichlorobenzene afforded the necessary ketone
(Scheme 1). A two step reductive amination using 4-chloroaniline
* Corresponding author. Tel.: +1 908 740 3462.
E-mail address: jack.scott@spcorp.com (J.D. Scott).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.11.075

J. D. Scott et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1278–1283
1279
O
N
N
NC
Cl
N
Cl
N
H
N
N
NH2
O
F3C
Cl
N N
Cl
N
N
H
N
NH
O
Cl
O
Cl
1 rimonabant
2 taranabant
3 otenabant
Figure 1.
R
O
Table 1
3
Binding affinities of piperidine and piperidinone analogs
N
X1
Z
F
X
Y
N
X2
F
Cl
Figure 2.
Cl
7a-7c, 8a-8c, 9
was followed by hydrolysis of the ester and subsequent lactam for-
mation to afford piperidinones 6a and 6b. Benzylation at the 3-po-
sition of the piperidin-2-ones provided both cis and trans
diastereomers. Reduction of the piperidinones afforded piperidines
8a–c. Compound 9 with a 2,4-dichlorophenyl substituent on the
piperidine nitrogen (pictured in Table 1) was prepared via aromatic
chlorination of piperidine 8a using sulfuryl chloride.
As summarized in Table 1, targets with the piperidine core had
improved affinity for the CB1 receptor17 compared to their corre-
sponding piperidinones. For example piperidine 8a had a sixfold
higher affinity for the CB1 receptor compared to the piperidinone
7a. This increased affinity may be due to an improved orientation
of the piperidine core substituents versus those substituents on
the piperidinone core. With respect to the relative stereochemistry
of these analogs, the trans piperidine 8a exhibited at least a 22-fold
higher affinity compared to the cis stereoisomer 8b.
To gain further understanding of the importance of stereochem-
istry in this series, stereoisomers 8a and 8b were mapped to the
previously mentioned pharmacophore model.14 Figure 3 shows
the overlay of the (R,R)-enantiomer of 8a and rimonabant to the
CB1 model. The two chlorophenyl rings matched the two aromatic
features, while the chlorine atom of the N-phenyl substituent and
the difluorophenyl group each matched one hydrophobic feature.
The hydrogen bond acceptor feature was absent in compounds
8a and 8b. Both enantiomers of 8a (trans configuration) matched
the pharmacophore quite well with the best mapped conformation
having a conformational energy of 0.7 kcal/mol above that of the
minimum energy conformation. The three phenyl rings were
nearly co-planar in this mapped conformation. Overall, the piperi-
dine core provided a nice scaffold for the crucial functional groups
to reach their desired 3D locations. Unlike the trans configuration,
Compound
X
Y
Z
Relative
stereochemistry
hCB1 Ki
(nM)
hCB2 Ki
(nM)
1
—
O
O
—
H
H
H
H
H
H
—
H
H
H
H
—
2.4
560
574
7a
7b
8a
8b
7c
8c
9
trans
cis
trans
cis
444
714
72
>1636
109
15
>1778
>1765
>1846
>1678
>1846
>1846
H2
H2
O
H2
H2 Cl
Cl trans
Cl trans
H
trans
467
in order to match the pharmacophore model both enantiomers of
the cis configuration (8b) needed to adopt high energy conforma-
tions with the piperidine ring in a twist form. The best mapped
conformation of the cis substituted piperidine had a conforma-
tional energy of 3.3 kcal/mol above the energy minimum. The extra
conformational energy penalty in 8b may account for the reduction
in affinity for the CB1 receptor.
Previously it has been reported18 that 2,4-dichloro substitution
of one of the phenyl substituents provided up to a 10-fold im-
proved affinity compared to the corresponding 4-chloro phenyl
analog. Compound 8c with the carbon linked 2,4-dichlorophenyl
substituent possessed sixfold improved binding affinity compared
to analog 8a. Dichloro substitution of the nitrogen linked phenyl
ring was detrimental to the binding affinity of compound 9 as
the affinity decreased fivefold compared to 8a. Further SAR inves-
tigations focused on the substitution at the 5-position of the opti-
mized trans piperidine core corresponding to analog 8c.
Hydroxymethylation of piperidinone 6b was accomplished via a
two step protocol (Scheme 2). Alkylation alpha to the carbonyl
Cl
Z
Z
Z
Z HN
F
X
N
f
d,e
CO2Me
O
N
a-c
F
Cl
Cl
Cl
Cl
Cl
Cl
4a Z = H
4b Z = Cl
( )-5a Z = H
( )-5b Z = Cl
( )-6a Z = H
( )-6b Z = Cl
( )-7a, 7b Z = H (trans, cis)
( )-7c
X = O
X = H
Z = Cl (trans)
g
( )-8a, 8b Z = H (trans, cis)
2 ( )-8c
Z = Cl (trans)
Scheme 1. Reagents and conditions: (a) Methyl 5-chloro-5-oxovalerate, AlCl3, 100 °C, 32% (Z = Cl) or glutaric anhydride, AlCl3, 47%; MeOH, H2SO4, reflux, 85% (Z = H); (b) 4-
chloroaniline, TsOHÁH2O, Dean–Stark, reflux; (c) NaBH4, MeOH, À30 °C; (d) 2 M LiOH (aq), MeOH; (e) SOCl2, pyridine, toluene, 52% Z = H (four steps), 43% Z = Cl (four steps); (f)
LDA or LHMDS; 3,4-difluorobenzyl bromide, 11–39%; (g) BH3ÁTHF complex, THF reflux, 61%.

1280
J. D. Scott et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1278–1283
benzene sulfonamide 14b both possessed similar single digit nano-
molar Ki’s (3.8 nM and 4.2 nM, respectively) towards the CB1
receptor. The acetamide analog 14d with a Ki of 42 nM was an
exception to this trend. This may indicate that the smaller alkyl
groups on the methylene linked analogs may not reach deep en-
ough into the hydrophobic pocket of the receptor. Molecular mod-
eling indicated, in both the methylene and ethylene linked series,
that one of the sulfonamide oxygens can match the hydrogen bond
acceptor feature of the CB1 pharmacophore model.
To determine the importance of the absolute stereochemistry
of these CB1 antagonists, the enantiomers of 14a were separated
via chiral HPLC.19 The faster eluting enantiomer 14f had a 16-
fold increased affinity compared to the slower eluting enantio-
mer 14g. The difference in affinities between enantiomers in this
piperidine series was not as profound as that observed with in
the previously reported pyrazoline series in which the enantio-
mers possessed ꢀ100-fold difference in affinities.9 The lack of
significant disparity between the affinities of enantiomers 14f
and 14g was not surprising as it had been previously noted that
both enantiomers of 8a oriented well in our pharmacophore
model. Also noteworthy is that all of the compounds listed in
Table 2 had moderate to high selectivity for the CB1 receptor
compared to the CB2 receptor.
Figure 3. Overlay of the (R,R)-enantiomer of 8a and rimonabant to the CB1
pharmacophore model. The pharmacophore features are represented by meshed
spheres. Aromatic ring features are represented by pairs of solid brown spheres;
hydrophobic features by cyan spheres; hydrogen bond acceptor by a pair of green
spheres. Nitrogen atoms are colored as dark blue, oxygen atoms are red, and the
halogen atoms are green. Carbon atoms of rimonabant are colored light blue, and
those of 8a are colored yellow.
As mentioned previously, alcohol 10 was a common intermedi-
ate in the preparation of several other types of analogs (Scheme 3).
Conversion to and displacement of the mesylate by N-Boc pipera-
zine was followed by deprotection and nitrogen substitution to af-
ford analogs 15a–15g. A two step oxidation of the alcohol to a
carboxylic acid was followed by amide bond formation to afford
the amide analogs 16a–16d. Finally, conversion of alcohol 10 to
sulfonamides 17a–17d was accomplished via a five step sequence
featuring the displacement of a mesylate with sodium sulfite and
chlorination to afford the sulfonyl chloride, followed by derivatiza-
tion with various amines.
The binding affinities of these three classes of analogs is sum-
marized in Tables 3–5. In the piperazine series (Table 3), the smal-
ler capping groups, acetyl and methane sulfonyl (15e and 15c,
respectively) had significantly less affinity for the CB1 receptor
compared to the tert-butyl carbamate analog 15a. The more
lipophillic branched alkyl analogs 15d, 15f and 15g had 10- to
50-fold improved affinities compared to 15c and 15e. The affinity
of compound 15g with the basic moiety in the lipophillic region
of the receptor was 4- to 7-fold less compared to the non-basic
counterparts 15a and 15f. The loss of affinity due to a basic piper-
azine substituent was also reported in a series of CB1 receptor in-
verse agonists based on a pyridine core.20
with benzyloxymethyl chloride afforded a separable 10:1 mixture
of trans:cis isomers. Cleavage of the benzyl group with boron tri-
bromide followed by reduction of the carbonyl provided alcohol
10. This alcohol provided a core with synthetic versatility that
was used to prepare several classes of analogs. Conversion to the
amine 11 was accomplished via azide introduction under Mitsun-
obu conditions followed by a Staudinger reduction of the resultant
azide. The amine was then substituted to afford a series of sulfon-
amides and amides. Homologation of the linker proceeded through
the conversion of alcohol 10 to the nitrile. Reduction of the nitrile
afforded the ethylene linked amine 13 which was further elabo-
rated to provide analogs to investigate the importance of this
linker.
In general, for the methylene linked analogs 12a–12f, the larger
substituents on the amine in both the amide and sulfonamide ser-
ies conferred higher affinities for the CB1 receptor (Table 2). For
example, the naphthyl sulfonamide 12d had a 69-fold improved
affinity compared to the cyclopropyl sulfonamide 12b. This trend
was not observed to as great an extent with the ethylene linked
series as most of the analogs had high affinity for the receptor.
For example, the cyclopropyl sulfonamide 14a and the 4-cyano-
R2N
H
Cl
Cl
HO
Cl
H2N
Cl
N
a-c
f or g
d,e
O
N
N
N
Cl
Cl
Cl
( )-10
Cl
( )-11
Cl
Cl
Cl
Cl
( )-6b
( )-12
h-j
H
H2N
R2N
Cl
Cl
f or g
N
N
Cl
Cl
Cl
Cl
( )-13
( )-14
Scheme 2. Reagents and conditions: (a) LDA; BOMCl, THF À78 to À50 °C, 52%; (b) BBr3, CH2Cl2, 0 °C, 88%; (c) BH3ÁTHF complex, THF, reflux 87%; (d) DIAD, PPh3, (PhO)2P(O)N3,
THF, 83%; (e) PPh3, THF, 60 °C; H2O, THF, 45 °C, 90%; (f) RSO2Cl, Et3N, CH2Cl2, 71–79%; (g) RC(O)OH, EDCI, HOBt, MeCN 36–87%; (h) MsCl, Et3N, CH2Cl2, rt, 99%; (i) KCN, 18-
crown-6, MeCN, reflux 16 h, 95%; (j) BH3ÁTHF complex, THF, reflux, 69%.

J. D. Scott et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1278–1283
1281
Table 2
Binding affinities of alkylene amino piperidines
n
R2HN
Cl
N
Cl
Cl
11, 12a-12f
13, 14a-14f
Compound
n
R2
H
hCB1 Ki (nM)
hCB2 Ki (nM)
11
1
133
>1846
O
S
Pr
12a
12b
12c
1
1
1
48
158
6
25%a
O
O
S
>1847
>1847
O
O
N
S
O
O
S
12d
12e
1
1
2.3
5%a
O
O
112
25%a
O
12f
13
1
2
2
5
1407
NC
H
61
3.8
>2220
>2220
O
S
14a
O
O
S
NC
N
14b
2
4.2
>2220
O
O
S
14c
14d
2
2
5.8
42
>2220
>2400
O
O
O
14e
2
2
5.1
>2450
NC
O
S
14fb
3.4
57
>2400
>2400
O
O
S
14gb
2
O
a
Percent inhibition measured at 1
lM.
b
Separated enantiomers of 14a. The absolute stereochemistry of these enantiomers was not determined. See Ref.19 for HPLC conditions.
The amidopiperidine series 16a–16d represented analogs simi-
CB1 receptor (Table 4) with no apparent benefit for larger more
lipophillic groups in this particular series.
In the sulfonamide linked series, the isobutyl and isopentyl
analogs, 17a and 17d, respectively, both had single digit nano-
lar to rimonabant with the hydrogen bond accepting amide car-
bonyl directly attached to the core ring. All four amidopiperidine
analogs showed similar double digit nanomolar affinities for the

1282
J. D. Scott et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1278–1283
O
R4N
H
Cl
N
Cl
HO
Cl
e-g
a-d
R3N
N
N
N
Cl
Cl
( )-15
Cl
Cl
Cl
Cl
( )-10
( )-16
a, h-k
O
R5R6N
O
S
Cl
N
Cl
Cl
( )-17
Scheme 3. Reagents and conditions: (a) MsCl, Et3N, CH2Cl2, rt; (b) N-Boc-piperazine, iPr2NEt, MeCN, reflux (59%, two steps); (c) 4 N HCl (dioxane), MeOH, rt, 83%; (d) RSO2Cl,
or RC(O)Cl, Et3N, CH2Cl2 or RCHO, NaBH(OAc)3, DCE; (e) (COCl)2, DMSO, À78 °C; Et3N À78 °C to rt, 90%; (f) AgNO3, NaOH, H2O, EtOH, 0 °C, 70%; (g) R4NH2, EDCI, HOBt, Et3N,
DMF, rt, 60–80%; (h) NaI, acetone, reflux, 40%; (i) Na2SO3, EtOH, H2O, 100 °C, 49%; (j) phosgene, DMF, toluene; (k) R5R6NH, CH2Cl2, 21–33% (two steps).
Table 3
Table 4
Binding affinities of piperazine analogs
Binding affinities of amido piperidines
O
R4N
H
Cl
N
Cl
R3N
N
N
Cl
Cl
Cl
Cl
15a-15g
16a-16d
Compound
R3
H
hCB1 Ki (nM)
hCB2 Ki (nM)
Compound
R4
hCB1 Ki (nM)
hCB2 Ki (nM)
O
15a
15b
8
>1846
>2000
16a
33
1578
O
554
16b
18
368
O
S
15c
690
>1846
16c
16d
63
33
>1846
1384
O
Cl
O
S
15d
15e
44
>2222
>1846
O
O
451
O
Table 5
Binding affinities of sulfonamide piperidines
15f
13
57
>2400
>1500
O
S
O
15g
R5R6N
Cl
N
Cl
molar affinities while the cyclohexyl analog 17b exhibited
slightly less affinity for the CB1 receptor (Table 5). The isobutyl
analog in the sulfonamide series, 17a, showed a fivefold im-
proved affinity compared to the isobutyl amide analog 16a with
Ki’s of 6.3 and 33 nM, respectively. In contrast, the cyclohexyl
substituted sulfonamide 17b had an affinity similar to that of
the corresponding cyclohexyl amide 16b. Generally, having a
short linker between the core and hydrogen bond acceptor pro-
vided piperidine analogs that were more potent than those with
the hydrogen bond acceptor linked directly to the core. As had
been observed with previous analogs, all of these antagonists
exhibited moderate to high selectivity for the CB1 receptor over
the CB2 receptor.
Cl
17a-17d
Compound
17a
–NR5R6
hCB1 Ki (nM)
hCB2 Ki (nM)
1915
H
N
6.3
35
16
H
17b
1246
N
17c
1189
N
H
N
17d
9.1
1275

J. D. Scott et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1278–1283
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Gaal, L. F.; Rissanen, A. M.; Scheen, A. J.; Ziegler, O.; Rössner, S. Lancet 2005, 365,
1389.
Percentage of food intake reduction in DIO mice
Compound Dose
(mg/kg)
Food intake reductiona
Plasma
conc.b
(ng/mL) (ng/g)
Brain
conc.b
2 h
4 h
6 h
24 h
5. Rinaldi-Carmona, M.; Barth, F.; Héaulme, M.; Shire, D.; Calandra, B.; Congy, C.;
Martinez, S.; Maruani, J.; Néliat, G.; Caput, D.; Ferrara, P.; Soubrié, P.; Brelière, J.
C.; Le Fur, G. FEBS Lett. 1994, 350, 240.
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Stribling, D. S.; Rosko, K.; Strack, A.; Marsh, D. J.; Feng, Y.; Kumar, S.; Samuel, K.;
Yin, W.; Van der Ploeg, L. H. T.; Goulet, M. T.; Hagmann, W. K. J. Med. Chem.
2006, 49, 7584; (b) Lin, L. S.; Ha, S.; Ball, R. G.; Tsou, N. N.; Castonguay, L. A.;
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Med. Chem. 2008, 51, 2108.
12f
14f
15f
17a
3
22
39
0
5
4
22
5
24
4
10
6
7
5
28
15
1
12
66
0
3
3
3
37 11 38 11 37
0
0
3
0
6
9
0
5
7
4
0
a
Bolded values were statistically significant (
treated mice.
q <0.05) compared to vehicle-
b
Total concentrations measured at the 24-h time point.
7. Griffith, D. A.; Hadcock, J. R.; Black, S. C.; Iredale, P. A.; Carpino, P. A.; DaSilva-
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To investigate the in vivo efficacy of these CB1 antagonists, four
of the previously described analogs were evaluated in a mouse DIO
model21 to determine the effectiveness in reducing food intake
over a 24-h period. These compounds were dosed orally at 3 mg/
kg and food intake was compared to vehicle-treated mice. As listed
in Table 6, the ethylene linked sulfonamide 14f was the most po-
tent of the piperidines tested, reducing food intake 38% at the
24-h time point when dosed at 3 mg/kg. The amide 12f exhibited
statistically significant food intake reduction (q <0.05) up to 6 h;
however, it was not effective at the 24-h time point. The reduced
efficacy of 12f compared to that of 14f can be accounted for by
the observed lower brain exposure and brain to plasma ratio at
24 h for 12f. The other two analogs, 15f and 17a, demonstrated
no significant reduction of food intake in this model. Poor pharma-
cokinetic profiles and/or the inability of the compounds to parti-
tion into the brain could be factors for the lack of observed
in vivo potency for these two compounds. Both of these com-
pounds showed very low plasma exposure and no brain exposure
at the 24-h time point.
In conclusion, a new class of CB1 receptor antagonists has been
described based on a 5-substituted 1,2-diaryl piperidine core. Sev-
eral of the compounds exhibited single digit nanomolar affinities
for the CB1 receptor with greater than 100-fold selectivity com-
pared to the CB2 receptor. The sulfonamide 14f also produced a ro-
bust reduction of food intake in a DIO mouse assay over a 24-h
period. Future reports will describe the evolution of a structurally
similar series with further improvements in binding affinity and
in vivo activity.
15. Results of in-house screen to be reported at a later date.
16. Sato, Y.; Yamada, K.; Nomura, S.; Ishida, R.; Yamamura, M. EP270093.
17. All Ki’s were based on two separate determinations, each run in duplicate. For
the procedures used to determine the Ki’s see Ref..14
18. (a) Lan, R.; Liu, Q.; Fan, P.; Lin, S.; Fernando, S. R.; McCallion, D.; Pertwee, R.;
Makriyannis, A. J. Med. Chem. 1999, 42, 769; (b) Meurer, L. C.; Finke, P. E.; Mills,
S. G.; Walsh, T. F.; Toupence, R. B.; Goulet, M. T.; Wang, J.; Tong, X.; Fong, T. M.;
Lao, J.; Schaeffer, M.-T.; Chen, J.; Shen, C.-P.; Stribling, D. S.; Shearman, L. P.;
Strack, A. M.; Van der Ploeg, L. H. T. Bioorg. Med. Chem. Lett. 2005, 15, 645.
19. Chiral HPLC conditions: Chiralpak AD column, solvent: 85:15 hexanes/
isopropylalcohol, UV detector: 254 nM.
20. Madsen-Duggan, C. B.; Debenham, J. S.; Walsh, T. F.; Toupence, R. B.; Huang, S.
X.; Wang, J.; Tong, X.; Lao, J.; Fong, T. M.; Schaeffer, M.-T.; Xiao, J. C.; Huang, C.
R.-R. C.; Shen, C.-P.; Stribling, D. S.; Shearman, L. P.; Strack, A. M.; MacIntyre, D.
E.; Van der Ploeg, L. H. T.; Goulet, M. T. Bioorg. Med. Chem. Lett. 2007, 17, 2031.
21. In vivo efficacy was determined by incorporation of a fed, diet-induced obese
(DIO) mouse model. Mice were dosed orally 1 h prior to dark onset. Food was
returned at dark onset and intake was measured at 2, 4, 6 and 24 h after food
presentation.
References and notes
1. Devane, W. A.; Dysarz, F. A.; Johnson, M. R.; Melvin, L. S.; Howlett, A. C. Mol.
Pharmacol. 1988, 34, 605.