Furo[2,3-b]pyridine-based cannabinoid-1 receptor inverse agonists: Synthesis and biological evaluation. Part 1

Article abstract of DOI:10.1016/j.bmcl.2009.12.065

The synthesis, SAR and binding affinities of cannabinoid-1 receptor (CB1R) inverse agonists based on furo[2,3-b]pyridine scaffolds are described. Food intake, mechanism specific efficacy, pharmacokinetic, and metabolic evaluation of several of these compo

Full text of DOI:10.1016/j.bmcl.2009.12.065

Bioorganic & Medicinal Chemistry Letters 20 (2010) 1448–1452
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Furo[2,3-b]pyridine-based cannabinoid-1 receptor inverse agonists:
Synthesis and biological evaluation. Part 1
a
a
a
John S. Debenham a, , Christina B. Madsen-Duggan , Richard B. Toupence , Thomas F. Walsh ,
Junying Wang a, Xinchun Tong a, Sanjeev Kumar b, Julie Lao c, Tung M. Fong c, , Jing Chen Xiao c,
Cathy R.-R. C. Huang c, Chun-Pyn Shen c, Yue Feng c, Donald J. Marsh c, D. Sloan Stribling d,
Lauren P. Shearman d, Alison M. Strack d, Mark T. Goulet a,à
*
a Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
b Department of Drug Metabolism, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
c Department of Metabolic Disorders, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
d Department of Pharmacology, 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:
The synthesis, SAR and binding affinities of cannabinoid-1 receptor (CB1R) inverse agonists based on
furo[2,3-b]pyridine scaffolds are described. Food intake, mechanism specific efficacy, pharmacokinetic,
and metabolic evaluation of several of these compounds indicate that they are effective orally active
modulators of CB1R.
Received 16 November 2009
Revised 15 December 2009
Accepted 15 December 2009
Available online 4 January 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
CB1R
Cannabinoid
Obesity
Inverse agonist
Furopyridine
Treatment options for morbidly obese patients are limited. Sur-
gical interventions while effective1 are often irreversible and are
associated with many risks2 that would not generally be associated
with a pharmaceutical agent. In fact, a study examining the six
month complication rate of bariatric surgeries from 2001–2002
found about 40% of patients had complications that required re-
hospitalization.3 With advances in laparoscopic techniques, among
other things, this rate has improved to 33% in the period of 2001–
2006.4 The unmet medical needs of this patient population still re-
quire reversible, risk appropriate treatment options.
CNS permeable inverse agonists/antagonists of the cannabi-
noid-1 receptor (CB1R)5 have been shown to be effective in reduc-
ing food intake with concomitant weight loss in both human6 and
other animal7 studies. In our previous reports,8 we disclosed the
SAR and lead optimization of a screening hit containing a pyridine
core arrayed by three hydrophobic domains. This was further opti-
mized by ring annulation leading to naphthyridinone 1 (Fig. 1)
which exhibited good acute efficacy (similar to that of taranabant)9
and had low clearance in rats and dogs.10 Further elaboration of the
core structure to pyrido[2,3-d]pyrimidine 2 and ultimately triazo-
lone 3 allowed for adequate in vivo efficacy in rats, but with greatly
improved clearance.11 Unfortunately, 3 suffered from low bioavail-
ability in both dog and monkey; precluding its further
development.
Since the N-linked heterobicyclic systems (e.g., 1 and 3) exhib-
ited improved efficacy for suppressing food intake relative to the
monocyclic pyridine core previously disclosed,11 we continued to
pursue modifications to the heterobicyclic scaffold. The goal in this
lead optimization was to improve the scaffold sufficiently to have a
compound with a pharmacokinetic (PK) and safety profile suitable
for human clinical evaluation with efficacy in a rat food intake
model comparable to the clinical candidate, taranabant. We were
particularly interested in avoiding the low clearance/long T1/2 that
1 displayed. Herein we describe our initial evaluation of the gen-
eral furo[2,3-b]pyridine structures 6 and 7.
Entry into the 6,5 ring system of the furopyridines was readily
* Corresponding author. Tel.: +1 732 594 5497; fax: +1 732 594 2210.
E-mail address: john_debenham@merck.com (J.S. Debenham).
accomplished using the previously described 2-pyridone
(Scheme 1).10 Deprotonation of 5 with Cs2CO3 afforded an ambi-
dent anion, which was alkylated with an -haloketone. This pro-
vided mixture of O- and N-alkylated products typically
5
Present addresses: Forest Research Institute, Jersey City, NJ 07311, USA.
Present addresses: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston,
a
à
a
MA 02115, USA.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.12.065

J. S. Debenham et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1448–1452
1449
Table 1
O
Binding affinity of compounds at the human CB1R and CB2R expressed as IC50 (nM)12
Cl
Cl
O
N
Cl
Cl
NH O
Cl
NH
NH2
O
N
N
N
O
R1
O
Cl
N
1
2
Cl
CB1R IC50 7.5 nM
6
X
Cl
CB1R IC50 6.0 nM
Cl
O
N
Compound
R1
X
CB1R
CB2R
NH
N
O
6a
6b
6c
6d
6e
6f
6g
6h
6i
Me
Et
Et
i-Pr
i-Pr
Ph
t-Bu
t-Bu
C(CH3)2OH
Cl
Cl
H
Cl
H
Cl
Cl
H
56
17
13
1.9
1.7
3.5
5.5
4.3
20
1000
360
1000
640
1300
440
440
NC
Cl
N
H
O
N
N
N
3
4
CF3
Cl
CB1R IC50 1.9 nM
MK-0364 (taranabant)
CB1R IC50 0.3 nM
1900
2100
H
Figure 1. Heterobicyclic and tricyclic Merck leads and MK-0364.
produced in a 1:1 to 4:1 ratio respectively. The desired O-alkylated
isomer could be purified from the reaction mixture or further
deprotonated causing intramolecular nucleophilic attack upon
the adjacent nitrile which provided the furopyridine of general for-
mula 6. The amino group of 6 was further elaborated into amides
and ureas by treatment with the appropriate acylating agent. Not
surprisingly, the amino group, in the form of a vinylogous amide,
was a poor nucleophile. For example, acylation with acetic anhy-
dride in acetic acid required heating to 80 °C for 2–3 h to get the
reaction to go to completion. This was the preferred route to com-
pound 7f since exposure of 6 (where X = H) to acetic anhydride
with base resulted in over acylation while treatment with acetyl
chloride led to less pure reaction mixtures, including over
acylation.
Human binding affinities (Tables 1 and 2) were determined
using a standard protocol and all compounds tested were found
to be functional inverse agonists of CB1R.12 One of the first com-
pounds prepared in this series was 6g. It shared the same trichloro
halogenation pattern as 1 and 2 and had similar potency (5.5 nM)
at CB1R (Table 1). With structural similarities to both 1, 2 and 3 we
were eager to evaluate 6g in vivo to determine its anorectic effects
in DIO (diet induced obese) rats (Table 3). Compound 6g was dosed
orally (PO) at 1 mg/kg and rats were monitored for 18 h to deter-
mine changes in body weight (BW) and ability to suppress food in-
take (FI) relative to vehicle control.9 Compound 6g suppressed FI
50% relative to vehicle control in addition to causing a 5 g loss in
BW relative to vehicle treated rats that gained 13 g. This was the
same FI response we saw with 3, but with only 1/3 the dose. Com-
Table 2
Binding affinity of compounds at the human CB1R and CB2R expressed as IC50 (nM)12
O
R2
Cl
NH
O
R1
O
N
7
Cl
Compound
R1
R2
CB1R
CB2R
7a
7b
7c
7d
7e
7f
t-Bu
t-Bu
t-Bu
t-Bu
i-Pr
C(CH3)2OH
C(CH3)2OH
Me
0.58
0.39
1.2
1.2
0.40
5.4
>2000
1970
3300
3400
5100
5400
5400
NMe2
CH2NHMe
CH2OH
CH2OH
Me
7g
CH2OH
4.3
pound 1 had previously shown a very strong FI response (À68% rel-
ative to vehicle at 3 mg/kg), but with a very long T1/2 in rats (>8 h).
Compound 3 had improved T1/2 in rats (5.6 h) relative to 1, but
had very little bioavailability (F%) in both dog (2.1%) and monkey
(9.7%). The pharmacokinetic properties of 6g are shown in Table 4.
The T1/2 of 6g decreased in both rats (4.6 h) and dogs (7.9 h) rela-
tive to 1. However, monkey showed fast clearance and a short T1/2
of 2.4 h with a low bioavailability of 11%. The high clearance of 6g
in monkey was not initially a concern as this compound showed
low metabolic stabilitywhenincubatedin monkeyliver microsomes
(only about 25% remaining after 60 min) while its response in
human microsomes was much more like that of rat and dog showing
little turnover (near 100% remaining after a 60 min incubation).
These results were consistent with the poor PK seen in monkey
(Table 4).
The metabolism of tritiated 6g was also explored. In rat plasma
parent compound was the major circulating species at 2, 6 and
24 h. However, in rat brain at all time points a hydroxylated
metabolite (presumably one of the methyls of the t-butyl group)
was observed in a 1:1 ratio with parent. This undesired level of
metabolite in the brain was further complicated by potentially
poor dose recovery. Excretion of tritiated 6g from bile-duct cannu-
lated rats was monitored for 120 h in IV (2 mg/kg) treated animals.
Bile and urine were examined and essentially the entire dose was
recovered in the bile. Total recovery was only 41% after 5 days.13
This was presumably due to the compounds lipophilicity mani-
fested by a high log D of 6.7.14
Cl
Cl
NH2
N
O
a
R1
O
N
H
O
N
5
6
X
Cl
X
Cl
O
R2=CH2Cl
R2
Cl
c
NH
R2=CH2NHMe
O
b
R2=CH2OAc
R2=CH2OH
R1
O
N
d
7
Cl
Scheme 1. Reagents and conditions: (a), a-haloketone, Cs2CO3 or K2CO3, DMF, rt to
65 °C, 45–80%; (b) RC(O)Cl or Ac2O/AcOH when R2 is Ac, MeCN, rt to 80 °C, 46–95%;
(c) CH3NH2, DMF, rt, 80%; (d) LiOHÁH2O, MeOH, THF, rt, 87%.

1450
J. S. Debenham et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1448–1452
Table 3
reductions to either an ethyl (13 or 17 nM CB1R for 6c and 6b)
or a methyl group (56 nM CB1R for 6a) resulted in lower activity.
The hydroxy isopropyl 6i showed a 4-fold loss of activity relative
to 6g but had improved solubility and log D (4.7 compared to 6.7
for 6g). Of interest was the fact that the 4-chloro of the dihalogen-
ated phenyl ring was not necessary for good binding, as the bis-
chloro analog 6h had essentially the same CB1R activity at
4.3 nM as 6g. None of the modifications at the 2-position of a
3-amino furopyridine were sufficient to improve the profile of a
compound like 6g sufficiently to advance further. However,
modifications to the 3-position of the furan ring (Table 2) led to
more significant changes.
DIO rat overnight (18 h) body weight change (g) and food intakea
Compound
D
BW
D
BW
% Food intake
suppression
(vehicle)
(compound)
6g
6h
7d
7e
+13
+8
+5
+5
+6
+10
+10
+10
À5
À4
53
33
24
37
47
28
41
72
À6
À7
7g
À7
7f (0.1 mpk)
7f (0.3 mpk)
7f
À1
À1
À13
a
BW = body weight. All rats were dosed at 1 mg/kg unless otherwise indicated.
Optimization of the 3-position began with acetylation of 6h.
This led to 7a with a 7-fold increase in CB1R potency (0.58 nM),
bringing the specificity of CB1R to CB2R to over 3400:1. Unfortu-
nately with the increase in potency came a decrease in solubility.
In fact the compound defied all attempts at formulation and
in vivo analysis was not possible. Installation of hetero atoms be-
came a necessity to improve the physicochemical properties (vehi-
cle solubility). Dimethyl urea 7b (0.39 nM CB1R) and sarcosine
amide 7c (1.2 nM) were more soluble than 7a, but showed only
7% and 11% bioavailability respectively in rat. Glycolamide 7d
showed improved log D (6.0) relative to 6g. The hydroxyl group
greatly improved solubility relative to 7a allowing for formulation
and a determination of in vivo properties. Examination of the gly-
colamide with the isopropyl ketone 6e provided 7e and a further
reduction in log D (5.7) with improvement in potency to 0.4 nM
at CB1R. Moving the hydroxyl group to the ketone position for
acetamide 7f resulted in a ninefold loss of potency to 5.4 nM at
CB1R relative to 0.58 nM for 7a. Bishydroxylated 7g showed about
the same potency at 4.3 nM as 7f however the log D dropped to 4.9.
It was observed that acylation of the 3-amino group resolved the
oxidative/photoinstability seen with amino compound 6g. The four
hydroxyl containing compounds were selected for further
evaluation.
All p values were 60.05. mpk = mg/kg.
Table 4
Pharmacokinetic profiles (monkey = Rhesus macaque)
Compound (animal) F (%) T1/2 (h) Clp (mL/min/kg) Rat B/P (lM)
6g (rat)
59
63
11
100
32
42
38
31
61
4.2
7.9
2.4
2.8
3.5
11
3.3
52
4.8
5.6
7.3
29
22
10
3.0
20
4.9
16
0.22/0.22 = 1.0
—
—
0.29/0.13 = 2.3
0.086/0.049 = 1.8
—
0.15/0.16 = 0.94
—
0.056/
0.072 = 0.77
—
—
6g (dog)
6g (monkey)
6h (rat)
7d (rat)
7d (dog)
7e (rat)
7e (dog)
7f (rat)
7f (dog)
7f (monkey)
7g (rat)
87
100
64
26
45
7.5
5.0
2.8
8.6
0.094/
0.147 = 0.64
—
—
7g (dog)
7g (monkey)
9
50
1.8
17
33
2.1
Brain/plasma (B/P) concentrations were determined at 4 h following 1 mg/kg IV
dosing.
Table 3 showed the acute food intake effects elicited after a
1 mg/kg oral dose. All compounds effectively suppressed FI and de-
creased BW gain relative to vehicle treated controls. Of the four, 7f
and 7g stood out, exhibiting the most robust effects. Even at a dose
as low as 0.1 mg/kg, 7f significantly suppressed 18-h FI and re-
duced BW in similar fashion to 7d, but at only one tenth the dose.
In vivo profiles of 7d–g (Table 4) were required to further differ-
entiate these compounds. Both 7d and 7e had good exposure in
rats with about the same 3.5 h T1/2. They also both exhibited con-
siderable deacylation with the corresponding 3-aminofuropyridine
metabolite circulating following PO administration in rats. In con-
trast, compounds 7g and 7f did not exhibit this behavior. While 7f
had a 4.8 h T1/2 in rats, it was long-lived in higher species showing
a one and two day T1/2 in dog and monkey, respectively. At this
point we focused our efforts on the evaluation of 7g as we viewed
the multi day T1/2 for 7f as too long.
While 7g had good bioavailability in both rats (64%) and mon-
key (50%) it exhibited fast clearance in dog with only 9% oral bio-
availability. To see if this would be problematic for human PK,
the metabolic stability of 7g was evaluated in liver microsome
incubations (Fig. 2). In the initial evaluation of oxidative metabo-
lism, 7g was incubated with liver microsomes for 60 min in the
presence of NADPH (data not shown). This experiment provided
no guidance as the compound showed little turnover in rat, dog,
monkey or human microsomes. However when the experiment
was repeated to also allow for glucuronidation [NADPH+ uridine
diphosphate glucuronic acid (UDPGA)] 7g was rapidly turned over
in only dog microsomes. This was consistent with the rapid clear-
ance seen solely in dog PK. Since this fast glucuronidation appeared
to be only associated with dog it did not appear to be a liability for
human testing.
Table 5
DIO rat 2 week efficacy following daily administration: body weight change (g) and
food intakea
Compound
D
BW
D
BW
% Food intake
suppression
(vehicle)
(compound)
6g
7d
7g
+29
+21
+24
+23
À3
À19
À2
19
19
24
21
Taranabant*
À3
a
BW = body weight. All rats were dosed at 1 mg/kg. All p values were 60.05.
14 day study: the study ended 18 h post dose day 14.
*
This study ended on day 13.
Further examination of the physical properties of 6g indicated
photo-oxidative instability in solution. After 40 h in an aqueous
pH 7.4 phosphate buffer solution exposed to air, 40 percent of
the material was observed to degrade to multiple products. This
was somewhat suppressed by a blanket of argon over the solution
resulting in a 15% loss of material to degradation while in solution.
The exact mechanism of the degradation was not investigated, but
it was clear there were several key deficiencies in this compound
that would need to be overcome to bring a compound forward
for further advancement. The most important of which would be
to improve the stability and dose recovery.
Continued optimization of this series was driven by the need to
increase stability and reduce the lipophilicity of 6g. Table 1 shows
the initial efforts. As the steric bulk of the t-butyl group at the
2-position was decreased, it was found that the isopropyl group
improved potency to about 2 nM in both 6d and 6e. Further

J. S. Debenham et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1448–1452
1451
120
100
80
60
40
20
0
40
35
30
25
20
15
10
5
0
-5
Vehicle
0.1 mg/kg
1 mg/kg
0.3 mg/kg
Rat
Dog
Monkey
Human
-10
-15
-20
0
1
2
3
4
5
6
7
Day
8
9 10 11 12 13 14
0
10
20
30
40
50
60
Incubation Time (min)
Figure 5. DIO Rat 2 week efficacy following daily administration of 7g at 0.1, 0.3,
and 1 mg/kg: body weight change (g).
Figure 2. Metabolic stability of 7g in liver microsomes.
(4) at 1 mg/kg which showed a 21% suppression in FI resulting in a
6.0% BW loss relative to vehicle treated rats in a similar 13 day
study. Compounds 6g (5.3% BW loss relative to vehicle) and 7d
(6% BW loss relative to vehicle) are also included in Table 5 for
comparison.
Compound 7g had a reduced log D value of 4.9 relative to 6.7 for
6g. To determine if this would result in improved dose recovery,
tritiated 7g was prepared and dosed IV to bile-duct cannulated rats
at 1 mg/kg. Radioactivity excretion17 measured as a percent of dose
was determined to be 87% in bile and 5% in urine, indicating
acceptable dose recovery for continued evaluation of the
compound.
In order to confirm that the anorectic effects displayed by 7g
were mediated through actions at CB1R, an overnight food intake
study15 using CB1R-deficient (Cnr1À/À) mice was conducted. After
appropriate dose selection in C57BL/6 wild-type mice,16 ad libitum
fed 14–16 week-old male mice (Cnr1+/+, n = 10; Cnr1À/À, n = 7)
were dosed orally with 7g at 1 mg/kg. Compound 7g significantly
inhibited overnight (18 h) FI (53% suppression, p <0.0001) (Fig. 3)
and inhibited BW gain (À0.79 g loss relative to 1.39 gain for vehi-
cle, p <0.0001) in wild-type (Cnr1+/+) mice (Fig. 4). 7g had no sig-
nificant effect on any of these parameters in Cnr1À/À mice. These
data demonstrate that the anorectic actions of 7g are mediated by
CB1R.
Off target activity of 7g was evaluated as well. It was shown not
to be a significant inhibitor of the cytochrome p450 enzymes (IC50
Chronic evaluation of 7g was carried out with oral dosing for
2 weeks in DIO rats. As Figure 5 indicates 7g showed a dose depen-
dent response in its ability to affect changes in BW. Dosing at
0.1 mg/kg proved ineffective, while 0.3 or 1 mg/kg significantly re-
duced BW gain relative to vehicle. At 1 mg/kg, 7g suppressed
cumulative FI 24% (p <0.005) resulting in a 4.3% BW loss relative
to vehicle treated rats. This was on par with our clinical candidate
in
>100. The activity of 7g in the hERG potassium channel assay
was determined to be 6.6 M IC50. This was followed up with an
in vivo readout of cardiac parameters carried out in anesthetized
dogs at a 1–3–10 mg/kg cumulative dose IV infusion (each dose in-
lM): CYP3A4 98, CYP2C9 17, CYP2D6 73, CYP2C19 43, CYP1A2
l
fused over 30 min). Plasma levels of 7g reached 50 lM by the end
of the infusion. No meaningful changes in mean arterial pressure,
heart rate, or ECG intervals (including QTc) were observed as com-
pared to vehicle treated animals. Finally, 7g was screened broadly
against a customized panel of 175 assorted radioligand binding
and enzymatic assays.18
6
4
Of concern was a hit in a rat ligand-gated ion-channel receptor
Vehicle
GABAA, showing an estimated IC50 of 1.8
electrophysiological evaluation of the effects of 7g on Ltk cells
expressing human 1b3c2 GABAA receptors indicated that it be-
haved as a partial agonist with an EC50 of about 700 nM with a
maximum efficacy of 18% at 3 M relative to maximum GABA
lM. In house patch clamp
*
2
7g
a
0
l
Cnr1+/+
Cnr1-/-
activity. Additionally the responses showed very slow kinetics rel-
ative to GABA. Currents induced by 7g were inhibited by GABA
receptor antagonists picrotoxin and bicuculline, suggesting activity
Figure 3. Overnight food intake with wild-type and CB1-deficient mice (* = p
<0.0001).
via the GABA binding site. Since c-aminobutyric acid (GABA) is a
major inhibitory neurotransmitter in the central nervous system,
it was of utmost importance to ascertain what if any effects
in vivo might occur by the modulation of GABAA by 7g. Initial eval-
uation in a rotarod19 assay at 100 times the MED in male Sprague
Dawley rats (orally dosed at 30 mg/kg) showed no visible effects
2
Vehicle
7g
1
0
with plasma and brain drug levels of about 0.5
mild symptoms occurred at 30 mg/kg (plasma 7
while at 100 mg/kg more pronounced hyperactivity, hyperreactiv-
ity and ataxia were observed (plasma 24 M, brain 6.5 M). With
lM. In CD1 mouse
l
M, brain 2.3 M)
l
-1
*
l
l
-2
Cnr1+/+
Cnr1-/-
these findings, further development of 7g was halted. Evaluation
of other furopyridines indicated that there was still reason for opti-
mism about this series as other compounds in this series such as 6g
Figure 4. Overnight body weight change with wild-type and CB1-deficient mice
(* = p <0.0001).

1452
J. S. Debenham et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1448–1452
Maes, A.; Rothenberg, P.; Cote, J.; Rosko, K.; Cummings, C.; Warrington, S.;
Boyce, M.; Gottesdiener, K.; Stoch, A.; Wagner, J. J. Clin. Pharmacol. 2008, 48,
418.
showed greatly reduced GABAA activity (about 22% inhibition at
10 M) and were devoid of adverse neurological effects after dos-
ing CD1 mice at 500 mg/kg.
l
7. Cota, D.; Marsicano, G.; Tschöp, M.; Grübler, Y.; Flachskamm, C.; Schubert, M.;
Auer, D.; Yassouridis, A.; Thöne-Reinecke, C.; Ortmann, S.; Tomassoni, F.;
Cervino, C.; Nisoli, E.; Linthorst, A. C. E.; Pasquali, R.; Lutz, B.; Stalla, G. K.;
Pagotto, U. J. Clin. Invest. 2003, 112, 423.
8. (a) Meurer, L. C.; Finke, P. E.; Mills, S. G.; Walsh, T. F.; Toupence, R. B.;
Debenham, J. S.; 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.; MacIntyre, D. E.; Van
der Ploeg, L. H. T.; Goulet, M. T. Bioorg. Med. Chem. Lett. 2005, 15, 645; (b)
Madsen-Duggan, C.; 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.; Shen, C.-P.;
Stribling, D. S.; Shearman, L. P.; Strack, A. M.; Van der Ploeg, L. H. T.; Goulet, M.
T. Bioorg. Med. Chem. Lett. 2007, 17, 2031.
9. Fong, T. M.; Guan, X.-M.; Marsh, D. J.; Shen, C.-P.; Stribling, D. S.; Rosko, K. M.;
Lao, J.; Yu, H.; Feng, Y.; Xiao, J. C.; Van der Ploeg, L. H. T.; Goulet, M. T.;
Hagmann, W. K.; Lin, L. S.; Lanza, T. J., Jr.; Jewell, J. P.; Liu, P.; Shah, S. K.; Qi, H.;
Tong, X.; Wang, J.; Xu, S. S.; Francis, B.; Strack, A. M.; MacIntyre, D. E.;
Shearman, L. P. J. Pharmacol. Exp. Ther. 2007, 321, 1013.
In summary, we have shown that the heterobicyclic furo[2,3-
b]pyridines exemplified by 7g and 7f are potent CB1R inverse ago-
nists that are effective in modulating feeding behavior to suppress
both FI and BW gain. These effects were determined to be
mechanism based. While the efficacy, physical properties, pharma-
cokinetics, drug metabolism and disposition were acceptable,
off-target GABAA activity in lead compound 7g prevented clinical
advancement. Further SAR studies to avoid GABAA activity, phar-
macological evaluation and safety profiling of alternative furopyri-
dine analogs will be reported in due course.
Acknowledgments
10. Debenham, J. S.; Madsen-Duggan, C. B.; Walsh, T. F.; Wang, J.; Tong, X.; Doss, G.
A.; Lao, J.; Fong, T. M.; Schaeffer, M.-T.; Xiao, J. C.; Huang, C. R.-R. C.; Shen, C.-P.;
Feng, Y.; Marsh, D. J.; 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. 2006, 16, 681.
11. Debenham, J. S.; Madsen-Duggan, C. B.; 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.; Hale, J. J.; Walsh, T. F. Bioorg.
Med. Chem. Lett. 2009, 19, 2591.
12. The reported binding results were an average of 2–8 independent
determinations (each done in replicate) which were normally within 50% of
the average value. For both the binding and functional assay conditions, see:
Felder, C. C.; Joyce, K. E.; Briley, E. M.; Mansouri, J.; Mackie, K.; Blond, O.; Lai, Y.;
Ma, A. L.; Mitchell, R. L. Mol. Pharmacol. 1995, 48, 443.
We thank Keith Wafford, Marie-Therese Schaeffer, Hugo M.
Vargas, Patricia B. Bunting, Erin McGowan, Doreen Cashen, Bill
Martin and William K. Hagmann for their contributions toward this
study.
References and notes
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13. Feces were not collected.
14. HPLC Log D values were determined at pH 7.3.
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15. C57BL/6 mice were purchased from Taconic Farms. Cnr1 knockout mice were
generated by the laboratory of Dr. Andreas Zimmer, National Institute of
Mental Health, NIH (Zimmer, A.; Zimmer, A. M.; Hohmann, A. G.; Herkenham,
M.; Bonner, T. I. Proc. Natl. Acad. Sci. 1999, 96, 5780) and generously provided
by him.
16. Experimental methods were similar to that described in Ref. 10 except 7g was
only dosed at 1 and 3 mg/kg based on its improved efficacy.
17. Rats were monitored for 120 h.
18. Discovery Pharmacology services provided by MDS Pharma Services, Taipei,
Taiwan.
19. A rotarod test is used to assess the rodent’s sensomotor coordination by
evaluating how long it can remain on a rotating rod with a steady or increasing
rate of rotation.