Potent benzimidazolone based human β3-adrenergic receptor agonists

Article abstract of DOI:10.1016/j.bmcl.2006.08.010

The synthesis and biological evaluation of a series of benzimidazolone β₃ adrenergic receptor agonists are described. A trend toward the reduction of rat atrial tachycardia upon increasing steric bulk at the 3-position of the benzimidazolone mo

Full text of DOI:10.1016/j.bmcl.2006.08.010

Bioorganic & Medicinal Chemistry Letters 16 (2006) 5691–5694
Potent benzimidazolone based human b3-adrenergic
receptor agonists
Don R. Finley, Michael G. Bell, Anthony G. Borel, William E. Bloomquist,
Marlene L. Cohen, Mark. L. Heiman, Aidas Kriauciunas, Donald P. Matthews,
Tania Miles, David A. Neel, Christopher J. Rito, Daniel J. Sall, Anthony J. Shuker,
Thomas W. Stephens, Frank C. Tinsley, Mark A. Winter and Cynthia D. Jesudason*
Lilly Research Laboratories, Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN 46285, USA
Received 12 June 2006; revised 25 July 2006; accepted 1 August 2006
Available online 22 August 2006
Abstract—The synthesis and biological evaluation of a series of benzimidazolone b3 adrenergic receptor agonists are described.
A trend toward the reduction of rat atrial tachycardia upon increasing steric bulk at the 3-position of the benzimidazolone moiety
was observed.
Ó 2006 Elsevier Ltd. All rights reserved.
The b3 adrenergic receptor plays an important role in
mediating lipolysis in white adipose tissue1 and thermo-
genesis in brown adipose tissue.2 It has been reported
that stimulation of this receptor induces a variety of
pharmacological effects such as an increase in fat oxida-
tion, enhancement of energy expenditure, and improve-
ment of glucose uptake in rodent models of obesity and
diabetes.3 It may not, however, play as dominant a role
in humans4 and despite the interest in this target, there
have only been mixed reports of clinical efficacy in hu-
mans.5 Recent reports suggest the use of b3 agonists as
therapeutics for gastrointestinal6 and urinary disease.7
As part of our b3 agonist program, we utilized parallel
synthesis to quickly synthesize and screen a number
of compounds. We identified compound 1 (Fig. 1) as a
agonist at the human b3 adrenergic receptor and
were interested in understanding the SAR around the
benzimidazolone ring.
2-Amino-3-nitrophenol (2, Scheme 1) was reacted with
(2S)-glycidyl 3-nitrobenzenesulfonate to provide the
epoxide (3) which was opened using dibenzylamine.
The aromatic nitro group was reduced to provide the
dianiline which was treated with triphosgene in a
biphasic solvent mixture (toluene/aqueous acid) to form
the benzimidazolone (5). The alcohol was protected as
the TBS ether. This material was deprotonated with
sodium hydride and treated with 1.5 equivalents of
iodomethane. Three methylated products (6–8) were iso-
lated by flash chromatography and the structures of the
monomethyl regioisomers assigned by NOESY and
ROESY NMR experiments. These compounds were
desilylated and debenzylated to give the desired amines
Although activation of b1 receptors is known to increase
heart rate, evidence has accumulated to suggest that
some b3 agonists may produce a chronotropic effect in
rat atria,8 and there has been considerable debate in
the literature as to the underlying mechanism of the ef-
fect.9 The presence of a fourth b adrenoceptor was pos-
tulated,10 though this is now widely believed to be a low-
affinity state of the b1 receptor.11 One of the goals of this
SAR was to minimize this in vitro atrial tachycardia.
Keywords: Beta 3 agonists; Obesity; Benzimidazolone; Tachycardia;
Beta 1 receptors.
*
Corresponding author. Tel.: +1 317 276 7984; fax: +1 317 277
7287; e-mail: jesudason_cynthia_d@lilly.com
Figure 1. Initial hit.
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.08.010

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D. R. Finley et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5691–5694
Scheme 1. Reagents and conditions: (a) (2S)-glycidyl 3-nitrobenzenesulfonate, K2CO3, acetone, reflux, 18 h, 99%; (b) Bn2NH, MeOH, reflux, 10 h,
78%; (c) Na2S2O4, NaHCO3, EtOH/H2O (2:1), rt, 16 h, 81%; (d) triphosgene, toluene/2 N HCl (3:5), rt, 14 h, 93%; (e) TBSCl, imidazole, DMF, rt,
18 h, 96%; (f) NaH, MeI, THF, 0 °C, rt, 18 h, see yields above; (g) TBAF, THF, 0 °C, 3–5 h, 60–96%; (h) 10% Pd/C, ammonium formate, MeOH,
1 h, 75–85%.
Scheme 2. Reagents and conditions: (a) Cs2CO3, DMF, rt, 18 h, 79%; (b) NaClO2, Me2SO, rt, 18 h, 31%; (c) NaH, DMF, 90 °C, 3 h, 32%;
(d) K2CO3, DMAC, 130 °C, 2.5 h, 44%.
Scheme 3. Reagents and conditions: (a) NaCNBH3, acetic acid, MeOH, rt, 24 h.
Scheme 4. Reagents and conditions: (a) ROCl or (RCO)2O, Et3N, CH2Cl2, 0 °C, rt, 18 h; (b) K2CO3, MeOH, rt, 2 h, 56–94%(two steps);
(c) BH3-Me2S, THF, 0 °C, rt, 2 h, 54–57%; (d) NaBH(OAc)3, HOAc, 1,2 dichloroethane, 18 h, 11–49%; (e) (2S)-glycidyl 3-nitrobenzenesulfonate,
K2CO3, acetone, reflux, 18 h, 60–73%; (f) EtOH, reflux, 18 h, 42–58%; (g) Na2S2O4, NaHCO3, EtOH/H2O (2:1), rt, 2 h; (h) triphosgene, toluene/2 N
HCl (3:5), rt, 18–72 h, 33–58% (two steps).
Scheme 5. Reagents and conditions: (a) 2-nitropropane, potassium tert-butoxide, diglyme, 130–150 °C, 4 h, 71%; (b) H2 (50 psi), 5% Pd/C, HOAc,
MeOH, 50 °C, 16 h, 86%; (c) 6-chloronicotinamide, K2CO3, DMAC/iso-octane (5:1), 140 °C, 6 h, 93%.

D. R. Finley et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5691–5694
5693
(9–11). Debenzylation of the protected amine (5) provid-
ed 4-(3-amino-2-hydroxy-propoxy)-1,3-dihydro-ben-
zoimidazol-2-one (12) as a comparator.
The ketones were synthesized as described in Scheme 2.
1-(4-Hydroxy-phenyl)-propan-2-one (13) was treated
with cesium carbonate and 4-fluorobenzaldehyde, and
the resulting aldehyde was then oxidized to give acid
(A). Similarly, nucleophilic aromatic substitution reac-
tions of the phenol (13) with 6-chloro-nicotinonitrile
and 6-chloro-nicotinamide provided ketones B and C,
respectively. A standard reductive amination protocol
between these amines and ketones was conducted in a
parallel fashion in combination with ion exchange puri-
fication as illustrated for fragments 12 and A in Scheme
3.12 An excess of the ketone (2 equiv) was utilized to en-
sure complete consumption of the starting amine
(1 equiv), so that the resulting product amine could be
obtained in >85% purity after ion exchange
chromatography.
A general synthetic route to allow for variation of the
substituent on the nitrogen is described in Scheme 4.
2-Amino-3-nitrophenol (2) was treated with excess acid
chloride or anhydride,13 and then the ester was selective-
ly hydrolyzed to provide the amide, which was reduced
with borane-dimethylsulfide complex to yield the substi-
tuted aniline (14). Alternatively, a reductive amination
of 2-amino-3-nitrophenol (2) with the corresponding
aldehyde yielded the aniline (14) in one chemical opera-
tion. This phenol was further elaborated to the epoxide
(15) as previously described, and this epoxide was
opened using amine 16. The benzimidazolone ring was
formed in an identical manner to that described in
Scheme 1 to yield the desired compounds (18).
The synthesis of the amine (16) is detailed in Scheme 5.
4-hydroxybenzyl alcohol (19) was treated with potassi-
um tert-butoxide and 2-nitropropane to afford 4-(2-
methyl-2-nitropropyl)phenol (20). The nitro group was
reduced by hydrogenation to provide the amine (21).
This phenol was then further elaborated via nucleophilic
aromatic substitution to the desired amine (16).
The biological results of the compounds prepared in this
parallel synthesis effort are reported in Table 1. The
compounds derived from amine 9 (i.e., 4-hydroxy-1,3-
dimethyl-1,3-dihydro-benzoimidazol-2-one), as well as
from amine 11 (i.e., 4-hydroxy-1-methyl-1,3-dihydro-
benzoimidazol-2-one) lose most of the b3 agonist activi-
ty of the parent unsubstituted compounds derived from
Table 1. Agonist activity of compounds at a concentration of 100 nM
expressed as % of the maximal response to isoproterenola
Amine
% of the maximal response to isoproterenol
Ketone
A
B
C
12
9
99
28
84
30
88
11
83
29
97
25
87
33
10
11
a Values are means of three experiments.

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D. R. Finley et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5691–5694
Table 3. Acute in vivo studies in diet-induced obese Long Evans rats
Compound
Dose (mg/kg po)
Respiratory quotient %
reduction over vehicle (20 h)
Energy expenditure %
increase over vehicle (20 h)
Exposureb
AUC(0–6h) (ng-h/mL)
18d
18f
10
10
22%a
29%a
9%a
18%a
342c
112
a
p < 0.05.
b Area under the plasma concentration curve determined over the duration 0–6 h in obese Long Evans rats following a 10 mg/kg po dose.
c Rat oral bioavailability (F344 rats) was found to be 8%.
3. (a) Hatakeyama, Y.; Sakata, Y.; Takakura, S.; Manda, T.;
Mutoh, S. Am. J. Physiol. 2004, 287, R336; (b) Kiso, T.;
Namikawa, T.; Tokunaga, T.; Sawada, K.; Kakita, T.;
Shogaki, T.; Ohtsubo, Y. Biol. Pharm. Bull. 1999, 22,
1073; (c) Atgie, C.; Faintrenie, G.; Carpene, C.; Buk-
owiecki, L. J.; Geloen, A. Comp. Biochem. Physiol. A:
Physiol 1998, A, 629.
4. (a) Arner, Peter. Best Pract. Res. Clin. Endocrinol. Metab.
2005, 19, 471; (b) Tavernier, G.; Barbe, P.; Galitzky, J.;
Berlan, M.; Caput, D.; Lafontan, M.; Langin, D. J. Lipid
Res. 1996, 37, 87.
5. (a) Van Baak, M. A.; Hul, G. B. J.; Toubro, S.; Astrup,
A.; Gottesdiener, K. M.; DeSmet, M.; Saris, W. H. M.
Clin. Pharmacol. Ther. 2002, 71, 272; (b) Larsen, T. M.;
Toubro, S.; van Baak, M. A.; Gottesdiener, K. M.;
Larson, P.; Saris, W. H. M.; Astrup, A. Am. J. Clin. Nutr.
2002, 76, 780.
amine 12. In contrast, the compounds derived from the
other monomethyl regioisomer (i.e., from amine 10) re-
tain most of the b3 agonist activity of the unsubstituted
benzimidazolone.
Further exploration of the substitution on this nitrogen
of this regioisomer yielded some interesting results. The
b adrenergic agonist data of these compounds are shown
in Table 2. These compounds are still potent agonists of
the b3 receptor with little or no agonist activity at the b1
or b2 receptors. However, these compounds showed dif-
ferential activity in their propensity to cause atrial
tachycardia in vitro.14 This effect is dependent on the
size of the substituent on the nitrogen with larger groups
showing a reduced propensity to cause tachycardia.
6. (a) Fletcher, D. S.; Candelore, M. R.; Grujic, D.; Lowell,
B. B.; Luell, S.; Susulic, V. S.; Macintyre, D. E. J.
Pharmacol. Exp. Ther. 1998, 287, 720; (b) Summers, R. J.;
Roberts, S. J.; Hutchinson, D. S.; Evans, B. A. Proc. West.
Pharmacol. Soc. 1999, 42, 115.
7. (a) Fujimura, T.; Tamura, K.; Tsutsumi, T.; Yamamoto,
T.; Nakamura, K.; Koibuchi, Y.; Kobayashi, M.; Yam-
aguchi, O. J. Urol. 1999, 161, 680; (b) Smith, C. P.;
Chancellor, M. B. Expert Opin. Ther. Pat. 2001, 11, 17.
8. (a) Kaumann, A. J.; Molenaar, P. Br. J. Pharmacol. 1996,
118, 2085; (b) Malinowska, B.; Schlicker, E. Br. J.
Pharmacol. 1996, 117, 943; (c) Cohen, M. L.; Bloomquist,
W.; Kriauciunas, A.; Shuker, A.; Calligaro, D. Br. J.
Pharmacol. 1999, 126, 10189; (d) Cohen, M. L.; Bloom-
quist, W.; Ito, M.; Lowell, B. B. Ion Channel 2000, 7, 17.
9. Brahmadevara, N.; Shaw, A. M.; MacDonald, A. . Br. J.
Pharmacol. 2003, 138, 99.
The pharmacological profiles of compounds 18d and 18f
were further assessed by measuring carbohydrate and
fat utilization in diet-induced obese Long Evans rats
by indirect calorimetry, measuring respiratory quotient
over a 24-h period.15 A single oral dose of these com-
pounds induced a decrease in respiratory quotient as
well as an increase in energy expenditure (Table 3). De-
spite this encouraging data, these compounds were
shown to have poor oral exposure (Table 3) and further
optimization to improve the in vivo properties of these
molecules will be reported in due course.
Acknowledgments
10. (a) Sarsero, D.; Molenaar, P.; Kaumann, A. J. Br. J.
Pharmacol. 1998, 123, 371; (b) Kaumann, A. J.; Preitner,
F.; Sarsero, D.; Molenaar, P.; Revelli, J.-P.; Giacobino, J.
P. Mol. Pharmacol. 1998, 53, 670.
The authors thank Mr. Jack Fisher and Mr. William
Trankle for the large-scale preparation of amine 16.
11. Kaumann, A. J.; Engelhardt, S.; Hein, L.; Molenaar, P.;
Lohse, M. Naunyn-Schmiedeberg’s Arch. Pharmacol. 2001,
363, 87.
12. (a) Siegel, M. G.; Shuker, A. J.; Droste, C. A.; Hahn, P. J.;
Jesudason, C. D.; McDonald, J. H.; Matthews, D. P., Jr.;
Rito, C. J.; Thorpe, A. J. Mol. Divers. 1998, 3, 113; (b)
Shuker, A. J.; Siegel, M. G.; Matthews, D. P.; Weigel, L.
O. Tetrahedron Lett. 1997, 38, 6149.
13. R = methyl was made via the mixed acetic/formic anhy-
dride as described in Krishnamurthy, S. Tetrahedron Lett.
1982, 23, 3315.
14. Rat atrial tachycardia was measured as described in Ref.
8c.
15. Chen, Y.; Heiman, M. L. Regul. Pept. 2000, 92, 113.
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