174
B. L. Palucki et al. / Bioorg. Med. Chem. Lett. 15 (2005) 171–175
Bednarek, M.; Weinberg, D.; Nargund, R.; Fong, T. M.
60
50
40
30
20
10
0
Annu. Rep. Med. Chem. 2003, 38, 31; (e) Gantz, I.; Fong,
T. M. Am. J. Physiol. Endocrinol. Metab. 2003, 284, E468;
(f) Zimanyi, I. A.; Pelleymounter, M. A. Curr. Pharm.
Des. 2003, 9, 1381; (g) Yang, Y. K.; Harmon, C. M.
Obesity Rev. 2003, 4, 239.
2. For rodent data, see: (a) Lu, D.; Willard, D.; Patel, I. R.;
Kandell, S.; Overton, L.; Kost, T.; Luther, M.; Chen, W.;
Woychik, R. P.; Wilkison, W. O.; Cone, R. Nature 1994,
371, 799; (b) Huszar, D.; Lynch, C. A.; Fair-Huntress, V.;
Dunmore, J. H.; Fang, Q.; Berkemeier, L. R.; Gu, W.;
Kesterson, R. A.; Boston, B. A.; Cone, R. D.; Smith,
F. J.; Campfield, L. A.; Burn, P.; Lee, F. Cell 1997, 88,
131.
-10
-20
5
10
20
40
Dose (mg/kg, p.o.)
Figure 1. Penile erections in conscious rat ex copula model. MB243
dose dependently increased the number of penile erections. Values
represent mean SEM. *p < 0.05, compared to vehicle treatment
(paired t-test). N = 10/dose.
3. For human data, see: (a) Gu, W.; Tu, Z.; Kleyn, P. W.;
Kissebath, A.; Duprat, L.; Lee, J.; Chin, W.; Maruti, S.;
Deng, N.; Fisher, S. L.; Franco, L. S.; Burn, P.; Yagaloff,
K. A.; Nathan, J.; Heymsfield, S.; Albu, J.; Pi-Sunyer, F.
X.; Allison, D. B. Diabetes 1999, 48, 635; (b) Farooqi, I.
S.; Yeo, G. S.; Keogh, J. M.; Aminian, S.; Jebb, S. A.;
Butler, G.; Cheetham, T.; OÕRahilly, S. J. Clin. Invest.
2000, 106, 271; (c) Lubrano-Berthelier, C.; Cavazos, M.;
Le Stunff, C.; Haas, K.; Shapiro, S.; Zhang, S.; Bougneres,
P.; Vaisse, C. Diabetes 2003, 52, 2996; (d) Lubrano-
Berthelier, C.; Le Stunff, C.; Bougneres, P.; Vaisse, C.
J. Clin. Endocrinol. Metab. 2004, 89, 2028.
4. For rodent data, see: (a) Wessells, H. Int. J. Imp. Res.
2000, 12, S74; (b) Lindia, J. A.; Nargund, R.; Sebhat, I.;
Weinberg, D.; Van der Ploeg, L. H. T.; MacIntyre, D. E.;
Martin, W. Int. J. Imp. Res. 2001, 13, S55; (c) Van der
Ploeg, L. H. T.; Martin, W. J.; Howard, A. D.; Nargund,
R. P.; Austin, C. P.; Guan, X.; Drisko, J.; Cashen, D.;
Sebhat, I.; Patchett, A. A.; Figueroa, D. J.; DiLella, A. G.;
Connolly, D. H.; Weinberg, D. H.; Tan, C. T.; Palyha, O.
C.; Pong, S.; MacNeil, T.; Rosenblum, C.; Vongs, A.;
Tang, R.; Yu, H.; Sailer, A. W.; Fong, T. M.; Huang, C.;
Tota, M.; Chang, R. S.; Stearns, R.; Tamvakopoulos, C.;
Christ, G.; Drazen, D. L.; Spar, B. D.; Nelson, R. J.;
MacIntyre, D. E. Proc. Natl. Acad. Sci. U.S.A. 2002, 99,
11381; (d) Martin, W. J.; McGowan, E.; Cashen, D. E.;
Gantert, L. T.; Drisko, J. E.; Hom, G. J.; Nargund, R.;
Sebhat, I.; Howard, A. D.; Van der Ploeg, L. H. T.;
MacIntyre, D. E. Eur. J. Pharmacol. 2002, 454, 71.
5. For human data on non-subtype selective MCR agonists,
see: (a) Wessells, H.; Fuciarelli, K.; Hansen, J.; Hadley, M.
E.; Hruby, V. J.; Dorr, R.; Levine, N. J. Urol. 1998, 160,
389; (b) Wessells, H.; Gralnek, D.; Dorr, R.; Hruby, V. J.;
Hadley, M. E.; Levine, N. Urologia 2000, 56, 641.
6. For recent patent reviews, see: (a) Bednarek, M. A.; Fong,
T. M. Expert Opin. Ther. Patents 2004, 14, 1; (b) Speak, J.
D.; Bishop, M. J. Expert Opin. Ther. Patents 2002, 12,
1631; (c) Wikberg, J. E. S. Expert Opin. Ther. Patents
2001, 11, 61; (d) Anderson, P. M.; Boman, A.; Seifert, E.;
Skottner, A.; Torbjorn, L. Expert Opin. Ther. Patents
2001, 11, 1583.
control rats also changed during the four days with a
decrease of À16 3g in the rats treated with dexfenflur-
amine (p < 0.01), and an increase of +15 2g in vehicle
treated rats.17
Further in vivo studies were performed to evaluate the
erectogenic activity of MB243 using an established
rodent model.4c,d The mean number of erections elicited
over a fifteen-minute time period, determined by a direct
visual count, in vehicle treated rats was 21.6 1.2,
n = 40. Erectogenic effects were investigated using a
within animal design in which each rat served as
its own control where the effect of compound was
compared to that produced by vehicle. Sixty minutes
following p.o. administration of MB243 (5–40mg/kg)
adose-dependent increase in erections was observed
(Fig. 1). The maximal increase in the number of erec-
tions (ꢀ35%) was detected at 20 and 40mg/kg, p.o.
In addition, iv administration of MB243 (3mg/kg) also
produced statistically significant increases in erectile
responses with a mean increase of 21.2 7.9% (p <
0.01; n = 10). The magnitude of the MC4R agonist-
induced erectile activity compared favorably to apomor-
phine (30.9 8.2%, p = 0.02, @ 0.025mg/kg, sc), a
known central initiator of erectile activity.18
In summary, we report the synthesis and evaluation of
MC4R agonists containing a piperazine side chain as
alternatives to the tetrahydroisoquinoline moiety. Struc-
ture–activity studies around the piperazine side chain
lead to the discovery of a potent and selective MC4R
agonist, MB243, which exhibits an excellent off-target
activity profile (IC50 or Ki > 1000nM) based on broad
screening performed at Panlabs versus >100 receptors,
enzymes, and ion channels.19 Finally, MB243 is effica-
cious in our animal models for both food intake and
erectile dysfunction.
7. (a) Dyck, B.; Parker, J.; Phillips, T.; Carter, L.; Murphy,
B.; Summers, R.; Hermann, J.; Baker, T.; Cismowski, M.;
Saunders, J.; Goodfellow, V. Bioorg. Med. Chem. Lett.
2003, 13, 3793; (b) Richardson, T. I.; Ornstein, P. L.;
Briner, K.; Fisher, M. J.; Backer, R. T.; Biggers, C. K.;
Clay, M. P.; Emmerson, P. J.; Hertel, L. W.; Hsiung, H.
M.; Husain, S.; Kahl, S. D.; Lee, J. A.; Lindstrom, T. D.;
Martinelli, M. J.; Mayer, J. P.; Mullaney, J. T.; OÕBrien, T.
P.; Pawlak, J. M.; Revell, K. D.; Shah, J.; Zgombick, J.
M.; Herr, R. J.; Melekhov, A.; Sampson, P. B.; King, C.
H. R. J. Med. Chem. 2004, 47, 744; (c) Xi, N.; Hale, C.;
Kelly, M. G.; Norman, M. H.; Stec, M.; Xu, S.;
Baumgartner, J. W.; Fotsch, C. Bioorg. Med. Chem. Lett.
2004, 14, 377.
References and notes
1. For recent reviews on melanocortin system, see: (a)
Martin, W. J.; MacIntyre, D. E. Eur. Urol. 2004, 45,
706; (b) Holder, J. R.; Haskell-Luevano, C. Med. Res.
Rev. 2004, 24, 325; (c) Voisey, J.; Carroll, L.; van Daal, A.
Curr. Drug Targ. 2003, 4, 586; (d) Sebhat, I.; Ye, Z.;