2960
R. J. Steffan et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2957–2961
Table 2. In vitro agonist activity at human b-AR’s for R variations of 15 when Ar=4-HO-phenyl
Compd
R
ꢀ3 EC50 nM (IA)
ꢀ1 EC50 nM (IA)
ꢀ2 (IA)
25
26
27
28
29
30
31
32
Hexyl
Octyl
Phenyl
Cyclohexyl
Isobutyl
58Æ10 (0.83)
49 (1.1)
135 (0.83)
60 (1.1)
126 (0.9)
29 (0.82)
20 (0.95)
26 (0.92)
10,900 (0.28)
887 (0.16)
489 (0.38)
1015 (0.29)
nt
1010 (0.24)
2050 (0.62)
(0.18)
0.2
0.02
0
0
nt
0
0
0.01
2,5-DiF-benzyl
3-(2-Thienyl)propyl–
2-Pyridyl–
See footnotes for Table 1.
Table 3. In vitro agonist activity at human b-AR’s for Ar and R variations of 15
Compd
Ar
R
ꢀ-3 EC50 nM (IA)
ꢀ-1 EC50 nM (IA)
bÀ2 EC50 nM (IA)
33
45 (0.83)
525 (0.19)
(0)
34
35
36
37
38
Octyl
306 (0.82)
1 (1.0)
nt
353 (049)
390 (0.63)
nt
nt
454 (0.7)
680 (0.26)
nt
Octyl
Octyl
Hexyl
5 (0.91)
55 (052)
10 (0.53)
nt
nt
See footnotes for Table 1.
over 400-fold selectivity over b2-AR. Compound 35 was
also in vivo active with an increase in thermogenesis of
18+2% at an ip dose of 10 mg/kg. Compound 35
however showed an increase in antagonistic activity at
b1-AR and b2-AR when compared to 26. (IC50=27 nM
versus 6156 nM at b1-AR and IC50=4 nM vs 268 nM at
b2-AR). The oxindole 37 and benzimidazole 38 analo-
gues had low EC50’s but the IA fell to around 50% of
isoproterenol. Compounds 37 and 38 also demonstrated
antagonism at b1-AR and b2-AR.
2. Bloom, J. D.; Dutia, M. D.; Johnson, B. D.; Wissner, A.;
Burns, M. G.; Largis, E. E.; Dolan, J. A.; Claus, T. H. J. Med.
Chem. 1992, 35, 3081.
3. Wilson, S.; Chambers, J. K.; Park, J. E.; Ladurner, A.;
Cronk, D. W.; Chapman, C. G.; Kallender, H.; Browne, M. J.;
Murphy, G. J.; Young, P. W. J. Pharm. Exp. Ther. 1996, 279, 214.
4. Susulic, V. S.; Frederich, R. C.; Lawitts, J.; Tozzo, E.;
Kahn, B. B.; Harper, M.-E.; Himms-Hagen, J.; Flier, J. S.;
Lowell, B. B. J. Biol. Chem. 1995, 270, 29483.
5. (a) b3-AR active compounds share a common pharmaco-
phore as reported by Mejean A.; Guillaume, J.-L.; Strosberg,
A. D. Eur. J. Pharm. 1995, 291, 359. (b) A subset of com-
pounds based on this template has been published by Bovy, P.
R.; Cecchi, R.; Venier, O. Int. Pat. Appl. WO 0144227, 2001.
Chem. Abstr. 2001, 135, 46110, Cecchi, R. Int. Pat. Appl.
WO0143744, 2001, Chem. Abstr. 2001, 135, 46105 and Cecchi,
R.; Croci, T.; Guzzi, U.; Marsault, E. Int. Pat. Appl. WO
9965895 1999, Chem Abstr. 1999, 132, 35618.
6. (a) Berridge, M. S.; Cassidy, E. H.; Terris, A. H.; Vesselle,
J. M. Nucl. Med. Biol. 1992, 19, 563. (b) Dubois, E. A.; van
den Bos, J. C.; Doornbos, T.; van Doremalen, P. A. P. M.;
Somsen, G. A.; Vekemans, J. A. J. M.; Janssen, A. G. M.;
Batink, H. D.; Boer, G. J.; Pfaffendorf, M.; van Royen, E. A.;
van Zwieten, P. A. J. Med. Chem. 1996, 39, 3260.
In conclusion, most analogues of the aryloxypropanol
aminomethylpiperidines of Figure 1 were identified as in
vitro potent and selective b3-AR agonists. Compounds
26 and 35 also induced thermogenesis in the in vivo
model and are potentially useful as antiobesity and
antihyperglycemic agents in humans.
References and Notes
1. (a) Dow, R. L. Exp. Opin. Invest. Drugs 1997, 6, 1811. (b)
Strosberg, A. D. Annu. Rev. Pharmacol. Toxic. 1997, 37, 421.
7. Mitsunobu, O.; Yamada, M. Bull. Soc. Chem. Jpn. 1967,
60, 2380.