F.-W. Sum et al. / Bioorg. Med. Chem. Lett. 13 (2003) 2191–2194
Table 1. b-AR activities of piperidine sulfonamide derivatives
2193
Compd
R1CH(OH)CH2NH2
Ar
b3-ARa EC50 mM (IA)b
b1-ARa EC50 mM (IA)
b2-ARa EC50 mM (IA)
76a
8
9
4-Methoxyphenyl
4-Methoxyphenyl
4-Methoxyphenyl
4-Butoxyphenyl
4-Butoxyphenyl
4-t-Amylphenyl
3,4-Dimethoxyphenyl
3,4-Dimethoxyphenyl
4-(Hexylureido)phenyl
4-(Hexylureido)phenyl
4-(Hexylureido)phenyl
2-Dibenzofuran
0.055 (0.74)
0.060 (0.88)
0.12 (0.72)
>2
0.85 (0.74)
0.92 (1.0)
0.02 (1.2)
0.09 (0.87)
>2
0.036 (0.74)
0.005 (0.82)
0.07 (0.64)
0.12 (0.88)
0.85 (0.75)
10.3 (0.46)
>100 (0.11)
>100 (0.32)
NT
>100 (0.04)
NT
>100 (0.14)
>100 (0.33)
NT
>100 (0.09)
>100 (0.03)
>100 (0.03)
NT
>100 (0.07)
NT
>100 (0.02)
>100 (0.01)
NT
6b
6c
6a
6b
6b
6b
6c
6a
6c
10
11
12
13
14
15
16
176d
18
19
20
NT
NT
0.012 (0.66)
NT
NT
0.92 (0.26)
NT
NT
6c
6d
6c
2-Dibenzofuran
4-Benzo-(2,1,3)-thiadiazole
NT
NT
aAgonistic activities were assessed bymeasuring cAMP levels in CHO cells expressing cloned human b-ARs; NT, not tested.
bIntrinsic activities (IA) were measured as fractions of the maximal response attained byisoproterenol.
Table 2. b-AR activities of pyrrolidine and azetidine sulfonamide derivatives
Compd
R1CH(OH)CH2NH2
Ar
b3-AR EC50 mM (IA)
b1-AR EC50 mM (IA)
b2-AR EC50 mM (IA)
26
276b
32
376a
38
6d
4-Butoxyphenyl
4-Butoxyphenyl
4-Butoxyphenyl
4-Butoxyphenyl
4-Butoxyphenyl
0.36 (0.79)
>2
1.1 (0.78)
0.03 (0.82)
>2
NT
NT
NT
1.6 (0.49)
NT
NT
NT
NT
0.92 (0.39)
NT
6d
6b
Within the piperidine series of compounds, the struc-
ture–activityrelationship varies with each of the four
aryloxypropanolamine and arylethanolamine (6a–6d)
investigated. For analogues containing 6a (7, 10, and
15), the smaller 4-methoxygroup in 7 is superior to both
4-butoxyand 4-hexylureido groups in conferring b3-AR
activity. A similar trend also prevails for the 6b deriva-
tives (8 and 13 are >15-fold more active than 11 and
12), albeit to a lesser extent. The 4-hexylureidophenyl
derivatives, 16 and 17, incorporating amines 6c and 6d,
respectively, have good b3-AR activities comparing to
the methoxysubstituted compounds 9 and 14. However,
as indicated bycompound 17, the selectivityagainst
b1-AR is onlymarginal. The analogues with tricyclic
and bicyclic aryl groups (18, 19, and 20) show moderate
b3-AR activities. In general, methoxy-substituted phe-
nylsulfonamides in the piperidine series are beneficial
for b3-AR activityand selectivityas exemplified by
compounds 7, 8, and 13.
sulfonamide derivatives, which will facilitate future
investigations.
Acknowledgements
We thank Drs. John Ellingboe, John Primeau, Eugene
Trybulski, and Kurt Steiner for their support of the
program, Drs. Tarek Mansour, and Dennis Powell for
proofreading and providing valuable suggestions, and
the Wyeth Discovery Analytical Chemistry group for
analytical and spectral determinations.
References and Notes
1. (a) Weyer, C.; Gautier, J. F.; Danforth, E. Diabetes Meta-
bolism 1999, 25, 11. (b) Pietri-Rouxel, F.; Strosberg, A. D.
Fundam. Clin. Pharmacol. 1995, 9, 211.
2. Recent reviews: (a) Arch, J. R. S. Eur. J. Pharmacol. 2002,
440, 99. (b) de Souza, C. J.; Burkey, B. F. Curr. Pharm. Design
2001, 7, 1433. (c) Kordik, C. P.; Reitz, A. B. J. Med. Chem.
1999, 42, 181. (d) Webber, A. E. Ann. Rep. Med. Chem. 1998,
33, 194. (e) Dow, R. L. Exp. Opin. Invest. Drugs 1997, 6, 1811.
3. Emorine, L. J.; Marullo, S.; Briend-Sutren, M.-M.; Patay,
G.; Tate, K.; Delavier-Klutchko, C.; Strosberg, A. D. Science
1989, 245, 1118.
Comparing the piperidine (11), pyrrolidine (27), and
azetidine (38) derivatives containing the aryloxy-propa-
nolamine 6b, the piperidine analogue shows better
b3-AR activity and good selectivity. Interestingly, for
analogues containing 6a, the azetidine 37 is superior to
the piperidine 10, and for analogues containing the
arylethanolamine 6d, the pyrrolidine 26 shows slightly
better b3-AR activity.
4. Liggett, S. B. Mol. Pharmacol. 1992, 42, 634.
5. 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.
6. (a) Yamanishi, T.; Chapple, C. R.; Yasuda, K.; Yoshida,
K.; Chess-Williams, R. Brit. J. Pharmacol. 2002, 135, 129. (b)
Yamaguchi, O. Urology 2002, 59, 25. (c) Tanaka, N.; Tamai,
T.; Mukaiyama, H.; Hirabayashi, A.; Muranaka, H.; Ishi-
kawa, T.; Akahane, S.; Akahane, M. Bioorg. Med. Chem.
2001, 9, 3265. (d) Morita, T.; Iizuka, H.; Iwata, T.; Kondo,
In conclusion, we have demonstrated that cyclic amine
sulfonamides, such as piperidine sulfonamide, are use-
ful linkers in designing human b3-AR agonists. Com-
pounds 7, 8, 13, and 37 were found to have potent
b3-AR activity, as well as high selectivity against b1-
AR and b2-AR. We have also developed efficient syn-
thetic routes for the preparation of these cyclic amine