Discovery of potent and orally bioavailable heterocycle-based β3-adrenergic receptor agonists, potential therapeutics for the treatment of obesity

Article abstract of DOI:10.1016/j.bmcl.2007.06.072

A novel series of heterocycle-based analogs were prepared and evaluated for their in vitro and in vivo biological activity as human β₃-adrenergic receptor (AR) agonists. Several analogs demonstrated potent agonist activity at the β₃-

Full text of DOI:10.1016/j.bmcl.2007.06.072

Bioorganic & Medicinal Chemistry Letters 17 (2007) 5245–5250
Discovery of potent and orally bioavailable heterocycle-based
b3-adrenergic receptor agonists, potential therapeutics for
the treatment of obesity
Jennifer A. Lafontaine,a,* Robert F. Day,a, Joe Dibrino,a John R. Hadcock,a
Diane M. Hargrove,a,à Michael Linhares,b Kelly A. Martin,a Tristan S. Maurer,b
Nancy A. Nardone,a David A. Tessb and Paul DaSilva-Jardinea
aDepartment of Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Groton, CT 06340, USA
bDepartment of Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Groton, CT 06340, USA
Received 8 March 2007; revised 21 June 2007; accepted 27 June 2007
Available online 30 June 2007
Abstract—A novel series of heterocycle-based analogs were prepared and evaluated for their in vitro and in vivo biological activity
as human b3-adrenergic receptor (AR) agonists. Several analogs demonstrated potent agonist activity at the b3-AR, functional selec-
tivity against b1- and b2-ARs, and favorable pharmacokinetic profiles in vivo. Compound 17 increased oxygen consumption in rats,
a measure of energy expenditure, with an ED20% of 2 mg/kg.
ꢀ 2007 Elsevier Ltd. All rights reserved.
The use of human b3-adrenoreceptor (b3-AR) agonists
to increase metabolic rate has been widely studied as a
potential approach for the treatment of obesity.1 Since
the identification of the b3-AR some 25 years ago,2 there
have been numerous reports of arylethanolamine-based
b3-AR agonists, structurally related to the endogenous
catecholamines adrenaline and noradrenaline (Fig. 1).
Early work in the investigation of b3-AR agonists
revealed that the incorporation of acidic functionality
can confer selectivity for the b3 receptor over the
b1- and b2-adrenoreceptors,3 as in BRL-37344
(Fig. 1, 1)4 and CP-331679 (2).5 This selectivity is essen-
tial to avoid unwanted effects on heart rate (b1-medi-
ated) and blood pressure (b2-mediated), and as a result
many of the b3 agonists reported to date contain a car-
boxylic acid or an acid isostere.6 Unfortunately, because
these compounds are zwitterionic and often very polar,
they are frequently reported to suffer from poor absorp-
tion and low oral bioavailability.7
Investigators at Merck have reported compounds in
which the carboxylic acid moiety is replaced by a less
acidic sulfonamide. Though many of these sulfonamides
possess excellent in vitro potency and selectivity profiles,
the potency is typically achieved at the expense of corre-
sponding increases in molecular weight and lipophilic-
ity.8 Subsequently, sulfonamides, such as clinical
candidate L-796568 (3, Fig. 2),9 suffer from low oral bio-
availability in preclinical species.10 As part of our efforts
to discover novel and selective b3-AR agonists which
also exhibit excellent pharmacokinetic properties, we
explored compounds which replace the acidic moiety
with neutral heterocycles, targeting compounds with
lower molecular weights and moderate clogP values.
We began our efforts by screening a number of heterocy-
cles as potential replacements for the carboxylic acid,
including imidazoles, triazoles, oxadiazoles, pyrazines,
thiazoles, and oxazoles, among others. While most of
the heterocycle replacements, as well as replacement
with a phenyl ring, led to greatly diminished potencies
at the b3-AR, we found that thiazoles and oxazoles were
well tolerated as carboxylic acid replacements.
Keywords: b3-Adrenergic receptor agonists; Obesity; Thermogenesis.
*
Corresponding author at present address: Pfizer Global Research
and Development, 10770 Science Center Drive, LaJolla, CA 92121,
USA. Tel.: +1 858 526 4866; fax: +1 858 526 4469; e-mail:
jennifer.lafontaine@pfizer.com
The synthesis of the thiazole-containing analogs is
described in Schemes 1 and 2. Starting from commer-
cially available 4, the phenyl ring was acetylated using
a standard Friedel–Crafts procedure.11 Bromination12
Present address: Novartis Institutes for Biomedical Research, Inc.,
Cambridge, MA 02139, USA.
Present address: Amylin Pharmaceuticals, LaJolla, CA 92121, USA.
à
0960-894X/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.06.072

5246
J. A. Lafontaine et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5245–5250
OH
H
OH
O
N
H
OH
Cl
N
H
HO
HO
N
R
N
OH
O
OH
O
H2N
N
O
1 BRL-37344
2 CP-331679
R = CH3 Adrenaline
R = H Noradrenaline
Figure 1. Adrenaline, noradrenaline, SmithKline Beecham’s b3-AR agonist BRL-37344, and Pfizer’s CP-331679.
OH
micromolar activity at the b3-AR (data not shown). We
therefore investigated other structural modifications to
improve the b3-AR potency of these analogs.
H
N
O
O
S
N
N
H
N
CF3
A survey of linkers between the amine and phenyl
group (attached to the heterocycle) revealed that
greatly improved potencies could be achieved by
replacing the two carbon linker of 9 with an ethoxy
linker, as in compound 16 (Scheme 2). The synthesis
of these analogs began with a Mitsunobu16 reaction
on phenol 12 to introduce the ethanolamine linker.
Bromination of the ketone, followed by cyclization
to the thiazole and Cbz-deprotection under acidic con-
ditions, gave amine 15. Treatment of 15 with epoxide
8 and reduction of the pyridyl chloride gave analogs
of structure 16.
S
3 L-796568
Figure 2. Merck’s L-796568.
of the resulting ketone, followed by treatment with a
thioamide at elevated temperature, afforded the thiazole
7. Utilizing known pharmacophore replacements for the
potentially metabolically labile catechol moiety of the
endogenous hormones, we prepared analogs with 3-pyridyl
and chlorosulfonamidephenyl-containing ‘head groups.’
Analogs 11 were constructed using the previously
reported N-{2-chloro-5-[(2R)-oxiran-2-yl]phenyl}methane-
sulfonamide,13 and the 3-pyridyl analogs were prepared
from 7 in a two-step procedure using epoxide 8.14
It was found that thiazoles bearing a range of small alkyl
or heterocyclic groups gave improved in vitro efficacy
and potency while retaining functional selectivity
against b1-AR and b2-AR (Table 2). In this series, the
pyridyl head group was found to be optimal, and 16a,
in which R = H, gave the best b3-AR potency
(EC50 = 27 nM, see Table 2). Methyl analog 16b, while
less potent (EC50 = 170 nm), had higher intrinsic agonist
activity (106%) than 16a. These analogs also possess
optimal physiochemical properties, as they are charac-
terized by excellent solubility,17 low molecular weights,
and moderate lipophilicity (for 16a: solubility >10 mg/
Table 1 describes thiazole-containing analogs of the
structures 9 and 11, many of which possess full agonist
activity at the b3-AR (relative to the full agonist isopro-
teronol). Though several of the analogs have good selec-
tivity over b1- and b2-ARs, even the most potent of these
analogs lack the low-nanomolar b3-AR potency of com-
pound 3. Replacement of the 3-pyridyl head group with
a 3-chlorophenyl moiety, which has been widely used in
the b3-AR agonist literature, gave compounds with only
O
O
O
Br
a
b
O
O
Me
N
H
Me
N
H
Me
OH
N
H
4
5
6
R
S
H
N
N
O
e,f
c,d
+
N
Cl
N
N
R
H2N
S
7
8
9
OH
H
O
S
O
H
N
H
N
O
S
N
e
7
+
O
O
N
Cl
Cl
R
S
10
11
Scheme 1. Reagents and conditions: (a) CH3COCl, AlCl3, CH2Cl2, 0 ꢁC to rt, 92%; (b) tetrabutylammonium tribromide, CH2Cl2/MeOH, (2:1), rt,
15 h, 83%; (c) RCSNH2 (1 equiv), EtOH, 80 ꢁC, 3 h, 90–100%; (d) concd HCl, 120 ꢁC, 6–12 h, 85–91%; (e) EtOH, 80 ꢁC, 76–88%; (f) ammonium
formate, 10% Pd/C, MeOH, 16 h, rt, 77–90%.

J. A. Lafontaine et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5245–5250
5247
O
O
O
CbzHN
Br
OH
b
CbzHN
CbzHN
HO
O
O
a
12
13
14
R
S
R
S
N
N
c, d
OH
H
N
1) 8, e
H2N
O
O
2) f
N
15
16
Scheme 2. Reagents and conditions: (a) PPh3, ADDP, toluene/THF, 0 ꢁC to rt, 16 h, 84%; (b) tetrabutylammonium tribromide, CH2Cl2/MeOH
(2:1), rt, 15 h, 90%; (c) RCSNH2 (1 equiv), EtOH, 80 ꢁC, 4 h, 58–74%; (d) anisole, methanesulfonic acid, CH2Cl2, 16 h, 80–89%; (e) EtOH, 90 ꢁC,
16 h, 75–80%; (f) ammonium formate, 10% Pd/C, MeOH, 16 h, rt, 90–93%.
Table 1. b-Adrenergic activities for thiazoles 9 and 1115
OH
H
N
Ar
N
R
S
Ar
R
b3-AR EC50 lM (IA,%)
b1-AR IA% @ 30 lM
b2-AR IA% @ 30 lM
3
0.003 (92)
1.36 (55)
2.25 (80)
2.74 (108)
1.19 (106)
4.49 (94)
1
6
1
7
9a
9b
9c
9d
9e
3-Pyridyl
3-Pyridyl
3-Pyridyl
3-Pyridyl
3-Pyridyl
Me
Et
7
9
Ph
3-Pyridyl
CF3
7
14
17
7
21
7
H
O
S
N
11a
11b
Me
Et
0.23 (121)
0.13 (95)
8
6
32
35
O
Cl
H
O
S
O
N
Cl
H
N
O
S
11c
Ph
0.49 (70)
6
19
O
Agonist activities were assessed by measuring cAMP levels in Chinese hamster ovary cells expressing cloned human b-ARs. Intrinsic activities (IA)
are expressed as a percentage of the maximal response of the full agonist isoproterenol. ND, not determined.
mL, MW = 341, and clogP = 1.71). Despite their selec-
tivity in the functional assay, all of the compounds had
b1-AR binding affinities in the submicromolar range,
which could potentially lead to heart rate lowering ef-
fects in vivo, though this outcome was not measured
for these compounds.
Increases in resting oxygen consumption in rats have
been widely used as a surrogate measure of energy
expenditure produced by b3-AR agonists.18 Both 16a
and 16b, when dosed orally, showed significant increases
in resting oxygen consumption over a 2 h period (Table
3).19 Compound 16b gave a greater change in oxygen
consumption than 16a, perhaps because 16b is more po-
tent at the rat b3-AR than 16a.
In vivo pharmacokinetic studies carried out on 16a
showed the compound to have a good profile in rat, with
a bioavailability of 53%, a moderate clearance (26 mL/
minꢀ1 kgꢀ1), and volume of distribution (1.1 L/kg).
Compound 16b was characterized by a similar clearance
(21 mL/minꢀ1 kgꢀ1) and volume (0.9 L/kg) in rat, but a
lower oral bioavailability (25%). In dog, 16b had an im-
proved bioavailability (53%), a higher volume of distri-
bution (5.0 L/kg), and moderate clearance (23 mL/
minꢀ1 kgꢀ1).
As we continued our investigations of heterocyclic
replacements for the acid moiety, we found that oxaz-
oles could be employed to confer potent and selective
b3-AR agonism. In particular, we have found that oxaz-
oles attached to the phenyl ring at the 4-position of the
oxazole were potent b3 agonists, as shown in Table 4,
while the two isomeric oxazole analogs were at least
10-fold less potent.

5248
J. A. Lafontaine et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5245–5250
Table 2. b-Adrenergic activities for series 16b
R
S
N
OH
H
N
O
N
16
R
Functional activitya
Binding Kib (lM)
c
b3-AR EC50 lM (IA, %)
b1-AR IA,% at 30 lM
b2-AR IA,% at 30 lM
b2 (KiH
)
b1
b1/b3
16a
16b
16c
16d
16e
16f
16g
16h
H
0.027 (85)
0.17 (106)
0.20 (150)
0.17 (106)
0.29 (159)
0.58 (53)
2
<5
<6
7
4
<5
9
0.01
0.12
NDd
ND
ND
0.50
ND
ND
0.14
0.10
0.10
0.037
0.13
0.15
0.12
0.097
14.2
0.80
—
Methyl
CF3
Ethyl
19
47
18
21
22
—
—
c-Pentyl
Phenyl
3-Pyridyl
4-Pyridyl
11
14
10
17
0.15
—
—
0.12 (121)
0.065 (106)
a Agonist activities were assessed by measuring cAMP levels in Chinese hamster ovary cells expressing cloned human b-ARs. IA, intrinsic agonist
efficacy, expressed as a percentage of isoproterenol maximum.
b Receptor binding assays were carried out with membranes from CHO cells expressing the cloned human receptor in the presence of 125I-
iodocyanopindolol.
c KiH, the inhibition constant for a drug representing the high affinity, agonist preferring binding site. Analysis of competition binding was best fit
using a two-site binding analysis.
d ND, not determined.
Table 3. Increase in rat oxygen consumption
tolerated, and modifications to the linker and pyridyl
head group typically resulted in diminished activity
or selectivity (data not shown). As in the thiazole ser-
ies, the –CH2CH2O– linker gave improved potencies
over the ethano linker.
D VO2 (0–120 min)
Rat b3-AR EC50 lM (IA, %)
3 mg/kg po 10 mg/kg po
16a 11%
16b 20%
ND
32%
0.026 (104)
0.013 (113)
Of these analogs, the most potent and selective com-
pound identified was compound 17. In the functional
cAMP assay, this compound is a full agonist at the b3-
AR (EC50 = 20 nM), and in the binding assay, com-
pound 17 has a KiH at b2 of 10 nM. It exhibits weak
binding affinity and exhibits antagonist properties at
the b1- and b2-ARs with no intrinsic agonist activity
(functional Kb’s: b1 > 500 nM, b2 > 1500 nM).20
Table 4. Oxazole isomers
R
OH
H
N
O
N
R
b3-AR EC50 lM (IA, %)a
The synthesis of compound 17 is shown in Scheme 3.
Starting from bromoketone 28,21 treatment with a neat
solution of formamide at elevated temperatures afforded
oxazole 29 in moderate yield. Demethylation with
methanesulfonic acid and methionine,22 followed by
alkylation with mesylate 3123, gave compound 32. In
this series it was found that the Mitsunobu reaction used
to alkylate the phenol in the thiazole series was not high
yielding, perhaps because compound 30 bears a less
acidic phenol than Mitsunobu substrate 12. Hydrogena-
tion led to the liberated primary amine 33, which was
treated with epoxide 814 to install the chiral ethanol-
amine of compound 34. Finally, hydrogenation to re-
move the chlorine on the pyridyl ring provided the
target compound 17 in good yield.
N
O
N
17
0.020 (94)
O
18
0.20 (98)
0.52 (24)
O
19
N
a Agonist activities were assessed by measuring cAMP levels in Chinese
hamster ovary cells expressing cloned human b-ARs. IA, intrinsic
agonist efficacy, expressed as
maximum.
a percentage of isoproterenol
A survey of alkyl substitution on the oxazole ring
(Table 5) showed that, as with the thiazoles, smaller
substituents conferring minimal steric bulk afforded
the best potencies. As shown in entries 26 and 27,
substitution on the 5-position of the oxazole led to a
dramatic drop in b3-AR activity. Similarly, alkyl
substitution on the adjacent phenyl ring was not well
Studies on compound 17 have shown this analog to have
an excellent PK profile in both rat and dog (see Table 6).
Based on this promising profile, 17 was progressed into
rat oxygen consumption studies, and was shown to in-
crease oxygen consumption at all doses tested (0.3, 1,
3, and 10 mg/kg of crystalline HCl salt), ranging from

J. A. Lafontaine et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5245–5250
Table 5. A survey of oxazole substitution
5249
R'
O
R
N
OH
H
N
O
N
R
R0
Functional activitya
Binding Kib (lM)
c
)
b3-AR EC50 lM (IA, %)
b1-AR IA, % at 30 lM
b2-AR IA, % at 30 lM
b2 (KiH
b1
b1/b3
17
20
21
22
23
24
25
26
27
H
Me
H
0.020 (94)
0.037 (111)
0.057 (133)
0.057 (135)
0.047 (110)
0.22 (137)
0.042 (94)
0.309 (80)
0.606 (75)
0
4
2
7
0.010
0.021
0.037
0.049
NDd
ND
0.20
0.40
0.40
0.36
0.21
0.05
0.27
0.17
1.55
20
19
11
H
Et
i-Pr
H
6
14
26
13
32
4
H
<10
8
7.4
CH2OCH3
CH2OBn
CH2OH
H
H
ND
ND
8.6
H
12
5
H
0.03
ND
Me
Me
2
0
ND
ND
Me
2
0
ND
a Agonist activities were assessed by measuring cAMP levels in Chinese hamster ovary cells expressing cloned human b-ARs. IA, intrinsic agonist
efficacy, expressed as a percentage of isoproterenol maximum.
b Receptor binding assays were carried out with membranes from CHO cells expressing the cloned human receptor in the presence of
125I-iodocyanopindolol.
c KiH, the inhibition constant for a drug representing the high affinity, agonist preferring binding site. Analysis of competition binding was best fit
using a two-site binding analysis.
d ND, not determined.
OMs
CbzHN
N
O
N
O
O
a
b
31
Br
c
HO
MeO
MeO
30
29
28
O
N
N
N
O
O
O
d
OH
Cl
N
8
H
N
H2N
CbzHN
O
O
O
e
Cl
N
O
33
34
32
N
O
OH
f
H
N
N
17
Scheme 3. Reagents and conditions: (a) formamide, 130 ꢁC, 65%; (b) MsOH, DL-methionine, 75–85%; (c) K2CO3, DMSO, 70%; (d) 10% Pd/C,
cyclohexadiene, 85%; (e) TMS acetamide, THF, reflux, 58%; (f) 10% Pd/C, ammonium formate, 85%.
Table 7. Increase in rat oxygen consumption for compound 17
(0–2 h)19
Table 6. Compound 17 pharmacokinetic profile
Rat
Dog
Dose (mg/kg)
Increase in oxygen consumption (%)
F (%)
66
1.4
13
0.89
59
5.1
6
0.3
1
8
11
29
42
2
1
4
6
t1/2 (h) (IV)
Cl (mL/min kg)
Vss (L/kg)
3
10
2.8
an 8% increase at the low dose to a 42% increase at
10 mg/kg (Table 7). The ED20% was determined to be
ꢁ2 mg/kg (1.6 mg/kg of active), which compares favor-
ably to data previously reported for b3-AR agonists in
rat oxygen consumption studies.24 Despite the signifi-
cant increases in oxygen consumption observed, only
relatively small increases in heart rate were observed in
rats (ca. 10% increase at the high dose of 10 mg/kg), a
finding which corroborates the in vitro selectivity data
for the compound.

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J. A. Lafontaine et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5245–5250
R.; Keohane, C. A.; Feeney, W. P.; Iliff, S. A.; Chiu, S. L.
Drug Metab. Disp. 2002, 30, 771.
11. Olah, G. A.. In Friedel–Crafts and Related Reactions;
Wiley: New York, 1963; Vols. 1 and 2.
12. Kajigaeshi, S.; Kakinami, T.; Okamoto, T.; Fujisaki, S. .
Bull. Chem. Soc. Jpn. 1987, 60, 1159.
13. Lafontaine, J. A.; Morgan, B. P. PCT Int. Appl. WO
2003072572, 2003.
14. Dow, R. L.; Schneider, S. R. European Patent Application
1138685, 2001. (R)-Toluene-4-sulfonic acid 2-(6-chloro-
pyridin-3-yl)-2-hydroxyethyl ester, described therein, was
treated with 1 M NaOH in THF and water to afford
epoxide 8 in 90% yield.
15. In all assays, each compound with an EC50 < 100 nM and
IA > 50% was tested at least twice in functional assays.
Similar potencies and intrinsic activities were observed in
the assays.
In conclusion, we have identified a novel series of potent
b3-AR agonists which lack the acidic moiety present in
most selective b3 agonists, demonstrating that thiazoles
and oxazoles are in this case viable pharmacophore
replacements for carboxylic acids. The reported com-
pounds were designed with moderate molecular weights
and lipophilicities to have drug-like physiochemical
properties, and several compounds show good pharma-
cokinetic profiles and in vivo efficacy in rats. Impor-
tantly, compound 17 has been shown to have minimal
heart rate effects in preclinical animal studies. Based
on their pharmacological and pharmacokinetic profiles,
these b3-AR agonists show promise as novel therapeu-
tics for the treatment of obesity.
16. Mitsunobu, O. Synthesis 1981, 1.
17. Solubility measurements were made in pH 6.5 phosphate
buffer.
Acknowledgment
18. Depocas, F.; Hart, J. S. J. Appl. Physiol. 1957, 10, 388.
19. Animals were removed from general housing in the
morning (7–7:30 am) and were deprived of food and
water for the length of the oxygen consumption
measurements. Animals were weighed (310–350 g),
marked, and placed into individual activity-monitored
chambers (1700 · 1700 · 500). The system was calibrated
and the run started (8:00–8:30 am). Oxygen consump-
tion measurements were made every 10 min for 3 h,
and then the animals were dosed with the test
compound or vehicle. Oxygen consumption measure-
ments were continued for 2 h. Oxygen consumption
values associated with periods of high ambulatory
activity (>100 counts/10 min) were excluded from all
calculations, as were the first five values of the run and
the first value after dosing.
20. Kb is the dissociation equilibrium constant for a compet-
itive antagonist (the concentration which would occupy
50% of the receptors at equilibrium).
21. For the preparation of 28, see: Ridge, D. N.; Hanifin, J.
W.; Harten, L. A.; Johnson, B. D.; Menschik, J.; Nicolau,
G.; Sloboda, A. E.; Watts, D. E. J. Med. Chem. 1979, 22,
1385.
The authors thank Dr. Robert Dow for helpful discus-
sions throughout the course of this work.
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6. For reviews of b2 agonists reported in the literature, see
Ref. 5 Weber, A. E. Ann. Rep. Med. Chem. 1998, 33, 193.
7. As described for: CP-331679 in Ref. 5 and for CL-316243
in Sum, F. W.; Gilbert, A.; Venkatesan, A. M.; Lim, K.;
Wong, V.; O’Dell, M.; Francisco, G.; Chen, Z.; Grosu, G.;
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S. N.; Urbina, A.; Camp, D.; Stankovic, N. Org. Process
Res. Dev. 2006, 10, 296.
23. Compound 31 was prepared in two steps from ethanol-
amine, which was first protected as the benzyl carbamate,
and then converted to the mesylate, under standard
conditions.
9. van Baak, M. A.; Hul, G. B. J.; Toubro, S.; Astrup, A.;
Gottesdiener, K. M.; DeSmet, M.; Saris, W. H. M. Clin.
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