Dihydro-pyrano[2,3-b]pyridines and tetrahydro-1,8-naphthyridines as CB1 receptor inverse agonists: Synthesis, SAR and biological evaluation

Article abstract of DOI:10.1016/j.bmcl.2010.04.071

Synthesis and structure-activity relationships of cannabinoid-1 receptor (CB1R) inverse agonists based on dihydro-pyrano[2,3-b] pyridine and tetrahydro-1,8-naphtyridine scaffolds are presented. Rat food intake and pharmacokinetic evaluation of 13g, 13i, 1

Full text of DOI:10.1016/j.bmcl.2010.04.071

Bioorganic & Medicinal Chemistry Letters 20 (2010) 3750–3754
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Dihydro-pyrano[2,3-b]pyridines and tetrahydro-1,8-naphthyridines as CB1
receptor inverse agonists: Synthesis, SAR and biological evaluation
a,
a
a
a
Christina B. Madsen-Duggan a, , John S. Debenham , Thomas F. Walsh , Lin Yan , Pei Huo ,
*
*
Junying Wang a, Xinchun Tong a, Julie Lao b, Tung M. Fong b, , Jing Chen Xiao b, Cathy R.-R. C. Huang b,
Chun-Pyn Shen b, D. Sloan Stribling c, Lauren P. Shearman c, Alison M. Strack c, Mark T. Goulet a,à
Jeffrey J. Hale 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
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis and structure–activity relationships of cannabinoid-1 receptor (CB1R) inverse agonists based
on dihydro-pyrano[2,3-b] pyridine and tetrahydro-1,8-naphtyridine scaffolds are presented. Rat food
intake and pharmacokinetic evaluation of 13g, 13i, 13k and 17a revealed these compounds to be highly
efficacious orally active modulators of CB1R.
Received 15 February 2010
Revised 13 April 2010
Accepted 16 April 2010
Available online 21 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Cannabinoid
CB1R
Inverse agonist
Dihydro-pyrano[2,3-b]pyridine
Tetrahydro-1,8-naphthyridine
Obesity
The cannabinoid-1 receptor is found predominantly in the CNS
and is activated by the endocannabinoids.1 An inverse agonist/
antagonist of the cannabinoid-1 receptor (CB1R)2 has the ability
to suppress food intake in both humans3 and other animals.4
CB1R inhibition has been demonstrated effective in treating
obesity.3
relative to maximum GABA activity). CNS adverse events, presum-
ably related to this GABA activity, were seen at levels 100 times its
MED of 0.3 mg/kg.5b At the same time efforts to eliminate the off
target activity of 2 were underway, we initiated a simultaneous ef-
O
Merck Research Laboratories have disclosed several series of
CB1R modulators where a central heterobicyclic scaffold was stra-
tegically flanked by hydrophobic domains (Fig. 1).5 Naphthyridi-
none 15a was our first bicyclic core and was found to effect
in vivo efficacy similar to that of MK-0364/taranabant; which has
been extensively studied in preclinical species and in humans
(Fig. 1).6 As compound 1 showed low clearance, an optimization ef-
fort in reducing the half-life led to furopyridine 2.5b While 2 had an
appropriate pharmacokinetic profile for clinical advancement, it
was later found to be a partial agonist of human GABAA receptors
O
HO
Cl
Cl
Cl
NH
N
O
O
NH
O
O
N
N
OH
1
2
Cl
Cl
CB1R IC50 7.5 nM
CB1R IC50 4.3 nM
Cl
O
R4
R5
R2
NC
Cl
N
H
(EC50 of about 700 nM with a maximum efficacy of 18% at 3 lM
R3
O
N
X
3
N
R1
Cl
X = O or NMe
* Corresponding authors. Tel.: +1 732 594 5497; fax: +1 732 594 2210.
E-mail address: john.debenham@merck.com (J.S. Debenham).
CF3
MK-0364 (taranabant)
CB1R IC50 0.3 nM
Present address: Forest Research Institute, Jersey City, NJ 07311, USA.
Present address: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston,
MA 02115, USA.
à
Figure 1. Early Merck leads, taranabant and core structure 3.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.04.071

C. B. Madsen-Duggan et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3750–3754
3751
Table 1
fort exploring the structurally related core 3. Herein, the synthesis
and structure–activity relationships (SAR) of the generalized bicy-
clic core 3 are described.
In order to probe the 2-position of the b face of the pyranopyri-
dine scaffold, our initial strategy involved the addition of vinyl
Grignard reagents to the cyano group of 4a7 or 4b5a (Scheme 1) fol-
lowed by intramolecular cyclization of the pyridone oxygen onto
the resulting vinyl ketone. This generated dimethyl ketones 5a–b,
and the monomethylated ketone 5d, in yields ranging between
11% and 58% (Table 1).
Structures and binding affinities of compounds at the human CB1R and CB2R
expressed as IC50 (nM), of the ketone derivatives 5a–l10
Cl
O
R3
N
O
R2
R1
Cl
Compound
R1
R2
R3
CB1R
CB2R
An alternative approach involved an aldol condensation strat-
egy. 3-Acetylpyridone 65a was treated with various ketones, and
pyrrolidine, at elevated temperatures using either conventional
or microwave heating (Scheme 1). This effort led to diethyl 5c,
mono i-propyl and t-butyl derivatives 5e and 5f and also the spiro-
annulated compounds 5h–j and 5l in yields ranging from 8% to
100% (Table 1). Pyridone 6 could also be treated with acetone
and DBU at elevated temperature affording 5a in 37% yield.8
Sulfide 5j was readily oxidized with magnesium bis(monop-
eroxyphthalate), providing sulfone analog 5k. To obtain the phenyl
derivative 5g, pyridone 6 was treated with 3-fluoro benzaldehyde
and NaOMe, affording the intermediate uncyclized phenyl 3-
hydroxypropanoylpyridone. The ketol was treated with tosic acid
5a
5b
5c
Cl
H
H
H
H
H
H
H
H
Me
Me
Et
H
H
H
Me
Me
Et
Me
i-Pr
t-Bu
47
120
15
1300
2300
4200
6300
3300
3400
>2000
3000
8300
5d, racemic
5e, racemic
5f, racemic
5g, racemic
5h
21
3.2
1.9
1.7
23
H
3-FPh
Spiro cyclopentyl
Spiro-cyclohexyl
5i
8.2
5j
H
H
H
4.9
15
8000
4100
>2000
S
5k
5l
S
O
O
in toluene at 120 °C, yielding predominantly the
a,b-unsaturated
ketone product, providing 5g in low yield (Scheme 1, Table 1).
The hydroxy analogs 7a and 7b were obtained by reacting 5a
with NaBH4 or methyl Grignard, respectively (Scheme 2, Table 3).
Treatment of 7a with NaH and MeI afforded ether 7c.
790
N
As noted previously,5 the amides in the structural series repre-
sented by 1 and 2 imparted significant potency and efficacy
enhancement. In order to evaluate both amide enantiomers, a race-
mic synthesis was used (Scheme 2). Ketones 5a or 5i were first
converted to the oxime, followed by reduction with zinc in acetic
acid affording the amines in about 80% yield. The spiroannulated
cyclohexyl amine was then treated with acid chlorides to generate
amides 12a or 8–10. Alternatively, either amine underwent PyBOP
coupling to yield amides 11, 12c–h and 13g–h (Tables 2 and 4).
The hydroxy amides, 12b and 13a–f, were synthesized by treating
the corresponding acetoxy amides 8–11 with NaOMe in MeOH. In
order to obtain ‘reversed’ amides 14a–d (Table 5), ketone 5a was
Cl
Cl
Cl
R4
O
O
O
R5
a or b
R3
a and c
N
N
R2
O
Cl
Cl
R1
Cl
O
O
Cl
7a R4 = OH, R5 = H
7b R4 = OH, R5 = Me
7c R4 = OMe, R5 = H
5a or 5i
CN
O
i-m
a
d-e
R3
f or g
N
N
H
R2
H
R1
Cl
R1
Cl
Cl
Cl
O
N
4a R1 = Cl, or
4b R1 = H
5a R1 = Cl, R2 = R3 = Me
5b R1 = H, R2 = R3 = Me
5d R1 = H, R2 = H, R3 = Me
HN
R
R
R3
Cl
Cl
N
O
N
O
R2
O
O
O
R1
Cl
Cl
Cl
b
See Table 2 and 4 for R
14a-d
R3
N
O
N
H
R2
8 R1 = H, R2,R3 = spiro cyclohexyl, R = CH2OAc
9 R1 = H, R2,R3 = Me, R = CH2OAc
H
Cl
H
Cl
10 R1 = Cl, R2,R3 = Me, R = CH2OAc
See Table 1 for R2 and R3
6
11 R1 = Cl, R2,R3 = Me, R = CH(CH3)2CH2OAc
5j R2R3
5k R2R3
=
=
S
S
d-e
N
h
Cl
12b R1 = H, R2,R3 = spiro cyclohexyl, R = CH2OH
13a-b R1 = H, R2,R3 = Me, R = CH2OH
c
O
O
O
13c-d R1 = Cl, R2,R3 = Me, R = CH2OH
O
13e-f R1 = Cl, R2,R3 = Me, R = CH(CH3)2CH2OH
H
H
Cl
Scheme 2. Reagents and conditions: (a) NaBH4, THF, 0 °C, 92%; (b) MeMgBr, THF,
0 °C, 14%; (c) MeI, NaH, DMF, rt, 28%; (d) HONH2ÁHCl, TEA, KOAc, MeOH, 70 °C; (e)
Zn, AcOH, 95 °C, (two steps), 86–95%; (f) RCOCl, TEA, CH2Cl2, rt, 40–84%; (g) RCO2H,
PyBOP, HOBt, DIPEA, DMF, rt, 39–80%; (h) NaOMe, MeOH, rt, (two steps), 78–81%;
(i) phenyl triflate, LiHMDS, DMF, À78 °C, 91%; (j) CO, Pd(dppf)Cl2ÁdiCH2Cl2, TEA,
MeOH, DMF, 70 °C, 81%; (k) Te, NaBH4, EtOH, AcOH, 70–20 °C, 65%; (l) 10% KOH,
THF, 70 °C, 96%; (m) NH4Cl or RNH2, PyBOP, HOBt, DIPEA, DMF, rt, 41–95%.
5g
F
Scheme 1. Reagents and conditions: (a) 1 equiv MeMgBr, R1R2C@CMgBr, THF, 2 M
HCl, rt, 11–58%; (b) R1R2CO, pyrrolidine, microwave heating, 150 °C or R1R2CO,
pyrrolidine, MeCN, 60 °C, 8–100%; (c) MMPP, CH2Cl2, MeOH, rt, 84%; (d) 3-
fluorobenzaldehyde, MeONa, THF, MeOH, rt, 75%; (e) TsOH, toluene, 120 °C, 7%.

3752
C. B. Madsen-Duggan et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3750–3754
Table 2
Table 5
Structures and binding affinities of compounds at the human CB1R and CB2R
Structures and binding affinities of compounds at the human CB1R and CB2R
expressed as IC50 (nM), of the spiro cyclohexyl amide derivatives 12a–h10
expressed as IC50 (nM), of the gem-dimethyl amide derivatives 14a–d10
O
H
Cl
O
N
R8
Cl
HN
O
R6
N
O
N
Cl
Cl
H
Cl
Compound
R8
H
CB1R
CB2R
Compound
R6
CB1R
CB2R
3900
4200
3200
12,000
1800
10,000
3600
14a, E1
14b, E2
14c, E1
14d, E2
97
220
14
2480
>2000
5150
7450
12a, racemic
12b, racemic
12c, E1
12d, E2
12e, E1
12f, E2
12g, E1
12h, E2
Me
CH2OH
C(CH3)2OH
1.3
0.3
0.7
18
0.4
13
CH(CH3)2CH2OH
150
(1S)-1-Ethanolyl
(1R)-1-Ethanolyl
E1 = Enantiomer 1; E2 = enantiomer 2.
0.2
2.0
3400
initially converted to the triflate and then carboxylated yielding
the unsaturated methyl ester. The unsaturated ester was reduced
with tellurium9 and NaBH4 and then saponified. The resulting sat-
urated acid was coupled to various amines with PyBOP yielding
14a–d.
E1 = Enantiomer 1; E2 = enantiomer 2.
It was of interest to examine the importance of the pyran oxygen
and its impact on binding affinity. The N-methyl amino derivatives
(tetrahydro-1,8-naphthyridine) 17a–d were readily prepared as
described previously except starting with the N-methyl pyridine
155a instead of pyridone 4a or 4b (Scheme 3, Table 6).
Table 3
Structures and binding affinities of compounds at the human CB1R and CB2R
expressed as IC50 (nM), of the gem-dimethyl amide derivatives 7a–d10
Cl
R4 R5
Binding affinities were determined using a standard protocol10
and all compounds tested were found to be functional inverse
agonists.
N
O
Our initial efforts focused on optimization of the R2 and R3 posi-
tions of 3. In general, as the size and hydrophobicity of these posi-
tions increased from methyl, so did the potency at CB1R (Table 1).
When R2 and R3 were both methyl there was little difference (2.6-
fold) in activity when R1 was chlorine 5a or hydrogen 5b. Interest-
ingly, the monomethylated 5d showed about a sixfold increase
compared to the corresponding 5b and an eightfold potency in-
crease was observed going from the dimethyl of 5b, to the diethyl
of 5C. Mono iso-propyl 5e, mono tert-butyl 5f and aryl 5g were
most potent at about 2–3 nM. The spiroannulated 5h, 5i, 5j and
5k all had potency in the 5–23 nM range while the spiroannulated
methyl piperidine was over 50-fold less active than sulfone 5k,
indicated a strong intolerance for basic groups at this position.
Even though 5e, 5f, and 5g showed a little more potency at
CB1R than achiral 5i, we wanted to minimize the complications
of including an extra chiral center. This led us to evaluate amides
in the spiro-cyclohexyl series first (Table 2). Racemic acetamide
showed a sixfold (relative to 5i) increase in potency to 1.3 nM
while the racemic glycolamide 12b exhibited a 27-fold CB1R po-
Cl
R4
Cl
R5
Compound
CB1R
CB2R
7a, racemic
7b, racemic
7c, racemic
7d, racemic
H
Me
H
OH
OH
OMe
NH2
130
80
19
4950
2920
3790
7760
H
110
Table 4
Structures and binding affinities of compounds at the human CB1R and CB2R
expressed as IC50 (nM), of the gem-dimethyl amide derivatives 13a–l10
O
Cl
R7
HN
O
N
R1
Cl
Compound
R1
H
R7
CB1R
CB2R
O
Cl
Cl
Cl
OR
13a, E1
13b, E2
13c, E1
13d, E2
13e, E1
13f, E2
13g, E1
13h, E2
CH2OH
CH2OH
46
>2000
10,130
4780
6610
570
7600
2460
5400
HN
N
360
1.7
670
2.1
34
R9
CN
NH
Cl
Cl
Cl
a-d
N
CH(CH3)2CH2OH
(CH3)2OH
N
Cl
Cl
Cl
1.7
14
15
See Table 6 for R
16 R9 = H, R = Ac
13i, E1
13j, E2
4.8
78
2260
5310
OH
OH
e
17a-b R9 = H, R = H
Cl
Cl
13k, E1
13l, E2
3.0
16
4750
3450
Scheme 3. Reagents and conditions: (a) (CH3)2C@CHMgBr or CH3C@CHMgBr, THF,
2 M HCl, rt, 59 %; (b) HONH2HCl, TEA, KOAc, MeOH, 70 °C; (c) Zn, AcOH, 95 °C, (two
steps), 88%; (d) AcOAcCl, TEA, CH2Cl2, rt, or
rt, 60%; (e) NaOMe, MeOH, rt, (two steps), 70%.
D-lactic acid, PyBOP, HOBt, DIPEA, DMF,
E1 = Enantiomer 1; E2 = enantiomer 2.

C. B. Madsen-Duggan et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3750–3754
3753
Table 6
Table 8
Structures and binding affinities of compounds at the human CB1R and CB2R
Pharmacokinetic profiles (rats)
expressed as IC50 (nM), of the gem-dimethyl amide derivatives 17a–d11
Compound
F
T1/2
Clp (mL/min/
kg)
Brain/plasma levels at 4 h
(lM)
O
(%)
(h)
Cl
OH
Brain/plasma ratio
HN
N
R9
12b
12c
13g
13k
17ª
13
0.8
1.9
13
34
62
3
0.027/0.016
1.7
0.116/0.033
3.5
—
—
0.122/0.321
0.38
0.076/0.086
0.88
6
85
N
Cl
Cl
100
25
7.9
4.2
4
Compound
R9
H
CB1R
CB2R
12
17a, E1
17b, E2
17c, E1
17d, E2
3.7
76
1.8
29
801
3390
1280
2330
Me
Brain/plasma concentrations were determined at 4 h following 1 mg/kg IV dosing.
E1 = Enantiomer 1; E2 = enantiomer 2.
obese (DIO) rats.5a The compounds were all dosed orally at 3 mg/
kg and the rats were monitored for 18 h and compared to vehicle
treated animals (Table 7). The cyclohexyl spiroannulated series
amide 12c showed a 28% reduction in suppressing overnight FI. All
of the dimethyl series amides showed very robust effects at reducing
BW and suppressing FI with 13i and structurally similar 13k show-
ing a remarkable 72% suppression of FI. The tetrahydro-1,8-naph-
thyridines, 17a and 17c were also effective at suppressing FI and
BW with the glycolamide showing a more robust FI suppression.
As a comparison, taranabant elicited a FI suppression of 49%6 at
3 mg/kg.
The pharmacokinetic properties for selected compounds are
displayed in Table 8.6 The cyclohexyl spiroannulated series repre-
sented by 12b and 12c had high clearance and poor oral bioavail-
ability (6–13%). Of note was compound 12c. Even though it had the
worst bioavailability (6%), and most rapid clearance (62 mL/min/
kg) of the group, its favorable B/P ratio (3.5) allowed for sufficient
CNS permeation to show FI and BW effects. Tetrahydro-1,8-naph-
thyridine 17a showed somewhat improved bioavailibity (25%),
while compounds 13g and 13k both had high oral bioavailability
(>80%) and robust half-lives (8–13 h). Not surprisingly these com-
pounds showed very robust actions on FI suppression and BW
changes.
tency enhancement. Additionally, 12b also displayed a 14,000-fold
selectivity over CB2R. Upon resolution of hydroxy amide analogs
12c–h a 10–30-fold preference for one enantiomer was observed
with the more active enantiomers all subnanomolar in activity at
CB1R. In the case of 12h even the less active enantiomer was still
quite potent at 2 nM for CB1R.
The compounds of Table 3 confirm the need for substitution at
the 4-position of the dihydropyrano ring. Hydroxy and amino com-
pounds 7a, 7b and 7d were poorly tolerated at about 80–130 nM
CB1R. Even methylation of the heteroatom such as methoxy 7c
showed improvement to 19 nM CB1R.
To determine if the spiro-cyclohexyl ring of amides 12a–h was
required for good binding, the gem-dimethyl pyranopyridine 5a
and 5b were also examined. There was a strong preference for
the tri-chloro substitution pattern (Table 4) as shown by the 25-
fold potency enhancement of 13c over the dichloro 13a. As was
the case for the spiroannulated series (Table 2), the hydroxy
amides with the gem-dimethyl substitution showed excellent
activity with a strong preference for one enantiomer (Table 4).
The 2-hydroxyacetamide 13c, 3-hydroxy-2,2-dimethylpropana-
mide 13e, dimethyl hydroxy 13g,
the -lactic acid analog 13k all showed similar activity (CB1R,
IC50 = 2–5 nM).
L-lactic acid derivative 13i and
D
Counterscreening of lead compounds 13g, 13i, 13k and 17a re-
vealed them to have potent activity in the hERG potassium ion
channel assay (380, 340, 120 and 40 nM IC50, respectively). Other
amides represented by Tables 2, 4 and 6 also had strong hERG
affinity (most <500 nM IC50). It should be noted that the hERG
activity of the amides was largely absent from the ketones of Table
Unlike the N-linked amides of Tables 2 and 4, the C-linked
amides of Table 5 were less well tolerated with the best, 14c, at
14 nM CB1R. The primary amides 14a and 14b ranged from about
100 to 220 nM.
Table 6 showed that the oxygen of the dihydropyrano ring could
be readily exchanged with N-methyl, as the resultant glycolamide
17a and (2R)-2-hydroxypropanamide 17c showed equivalent po-
tency with the pyran series analogs. Again there was a large pref-
erence for one enantiomer as has been shown with the other N-
linked amides.
1, many of which were >3–10 lM IC50.
In summary, we have shown that both dihydro-pyrano[2,3-
b]pyridine and tetrahydro-1,8-naphthyridine bicyclic core struc-
tures, (exemplified by 13g, 13i, 13k and 17a) are orally effective
modulators of food intake and body weight in a rodent model of
feeding. While these compounds have excellent CB1R activity, they
also possess considerable hERG affinity as well. Our efforts to
attenuate this hERG activity will be the subject matter of another
report.11
Several compounds were selected for evaluation of their effects
on food intake (FI) and body weight (BW) changes in diet-induced
Table 7
Rat food intake/body weight change (g) overnight (18 h)a
References and notes
Compound
D
Body weight
D
Body weight
% Food intake
suppression
(control)
(compound)
1. Finer, N.; Pagotto, U. Br. J. Diab. Vasc. Dis. 2005, 5, 121.
2. For a review see: Jagerovic, N.; Fernandez-Fernades, C.; Goya, P. Curr. Top. Med.
Chem. 2008, 8, 205.
12c
13g
13i
13k
17a
17c
+7
+5
+5
+5
+6
+6
+3
À11
À19
À16
À8
28
48
72
72
55
24
49
3. Després, J.-P.; Golay, A.; Sjöström, L. N. Engl. J. Med. 2005, 353, 2121.
4. Cota, D.; Marsicano, G.; Tschöp, M.; Grubler, 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.
5. (a) 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,
À5
Taranabant +10
À10
a
All rats were dosed at 3 mg/kg. The effects of all compounds were significant
compared to control (p <0.05).

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A. M.; MacIntyre, D. E.; Van der Ploeg, L. H. T.; Goulet, M. T. Bioorg. Med.
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. and 1755.
8. All of the reactions described herein are unoptimized.
Chem. Lett. 2006, 16, 681; (b) Debenham, J. S.; Madsen-Duggan, C. B.;
Walsh, T. F.; Toupence, R. B.; Wang, J.; Tong, X.; Sanjeev, K.; Lao, J.; Fong;
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.; Goulet, M. T. Bioorg. Med. Chem. Lett.
2010, 20, 1448.
9. Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans. 1 1975, 1574.
10. The reported binding results were the average of 2–8 independent
determinations (each done in replicate) which were normally within 50% of
the average value. For both the binding and the 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.
11. Yan, L.; Huo, P.; Debenham, J. S.; Madsen-Duggan, C. B.; Lao, J.; Chen, R.; Xiao, J.
C.; Shen, C.-P.; Stribling, D. S.; Sherman, L. P.; Strack, A. M.; Tsou, N.; Ball, R. G.;
Wang, J.; Tong, X.; Bateman, T. J.; Reddy, V. B. G.; Fong, T. M.; Hale, J. J. J. Med.
Chem. 2010, doi:10.1021/jml00023j.
6. 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.; J.C.; Goulet, M. T.;
Hagmann, W. K.; Lin, L. S.; Lanza, T. J., Jr.; Jewel, 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. Pharm. Exp. Ther. 2007, 321, 1013.
7. Meurer, L. C.; Finke, P. E.; Mills, S. G.; Walsh, T. F.; Toupence, R. B.; Debenham, J.
S.; Goulet, M. T.; Wang, J.; Tong, X.; Fong, T. M.; Lao, J.; Schaeffer, M.-T.; Chen, J.;