3672
W.-L. Wu et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3668–3673
CN
potent as their corresponding amide analogues. These
results are very encouraging and will be exploited in fu-
ture designs.18
Br
Br
O
NH2
NH2
In summary, we have successfully replaced the urea moi-
ety of our lead structure, 1, with isosteric amide and
benzimidazole groups to generate novel MCH antago-
nists. Extensive SAR exploration with various linkers
as well as the substituent effects led to the discovery of
many potent and selective MCH-R1 antagonists, such
as compounds 10a–f, 11a–e, and 26a–b.
b
a
N
N
N
Boc
29
Boc
Boc
31
30
CN
F
F
Cl
N
N
Cl
N
H
H
Acknowledgments
Cl
32
N
N
H
c
We thank Dr. Michael P. Graziano, Dr. Margaret Van
Heek, and Dr. John W. Clader for their support and
helpful discussions. We thank Dr. Briendra Pramanik’s
group and Dr. Tse-Ming Chan’s group for analytical
support.
33a R = Boc
33b R = H
33c-d
d
N
R
e
Scheme 8. Reagents and condition: (a) NH4OAc, NaCNBH3, MeOH,
room temperature, 90%; (b) 3-cyanophenylboronic acid, Pd(PPh3)4,
2 N Na2CO3, toluene–MeOH (1:1), reflux, 57%; (c) K2CO3, MeCN,
room temperature, 60%; (d) TFA–DCM (1:1), 100%; (e) cyclopropyl-
carboxyaldehyde or cyclopentanone, NaBH(OAc)3, DCM.
References and notes
1. Carpenter, A. J.; Hertzog, D. L. Expert Opin. Ther.
Patents 2002, 12, 1639.
2. (a) Chambers, J.; Amers, R. S.; Bergsma, D.; Muir, A.;
Fitzgerald, L. R.; Hervier, G.; Dytko, G. M.; Foley, J. J.;
Martin, J.; Liu, W.-S.; Park, J.; Ellis, C.; Ganguly, S.;
Konchar, S.; Cluderay, J.; Leslie, R.; Wilson, S.; Sarau, H.
M. Nature 1999, 400, 261; (b) Saito, Y.; Nothacker, H.-P.;
Wang, Z.; Lin, H. S.; Leslie, F.; Civelli, O. Nature 1999,
400, 265.
3. (a) Collins, C. A.; Kym, P. R. Curr. Opin. Invest. Drugs
2003, 4, 386; (b) Dyke, H. J.; Ray, N. C. Expert Opin.
Ther. Patents 2005, 15, 1303.
4. (a) Qu, D.; Ludwig, D. S.; Gammeltoft, S.; Piper, M.;
Pelleymounter, M. A.; Cullen, M. J.; Mathes, W. F.;
Przypek, R.; Kanarek, R.; Maratos-Flier, E. Nature 1996,
380, 243; (b) Chen, Y.; Hu, C.; Hsu, C. K.; Zhang, Q.; Bi,
C.; Asnicar, M.; Hsiung, H. M.; Fox, N.; Slieker, L. J.;
Yang, D. D.; Heiman, M. L.; Shi, Y. Endocrinology 2002,
143, 2469; (c) Ludwig, D. S.; Tritos, N. A.; Mastaitis, J.
W.; Kulkarni, R.; Kokkotou, E.; Elmquist, J.; Lowell, B.;
Flier, J. S.; Maratos-Flier, E. J. Clin. Invest. 2001, 107,
379; (d) Shimada, M.; Tritos, N.; Lowell, B.; Flier, J.;
Maratos-Flier, E. Nature 1998, 396, 670.
Table 5. SAR of benzimidazole analoguesa
CN
X
N
N
H
N
Bn
Compound
X
MCH Ki (nM)
28a
28b
28c
28d
3-Cl, 4-F
4,6-Cl,Cl
3,5-Cl,Cl
4-F,5-CF3
46
53
26
92
a See Table 1 notes.
Table 6. SAR of benzimidazole analogues (Cont’d)a
5. (a) Su, J.; McKittrick, B. A.; Tang, H. Q.; Czarniecki, M.;
Greenlee, W. J.; Hawes, B. E.; O’Neill, K. Bioorg. Med.
Chem. 2005, 13, 1829; (b) Souers, A. J.; Gao, J.; Brune,
M.; Bush, E.; Wodka, D.; Vasudevan, A.; Judd, A. S.;
Mulhern, M.; Brodjan, S.; Dayton, B.; Shapiro, R.;
Hernandez, L. E.; Marsh, K. C.; Sham, H. L.; Collins,
C. A.; Kym, P. R. J. Med. Chem. 2005, 48, 1318; (c)
McBriar, M. D.; Guzik, H.; Xu, R.; Paruchova, J.; Li, S.
J.; Palani, A.; Clader, J. W.; Greenlee, W. J.; Hawes, B. E.;
Kowalski, T. J.; O’Neill, K.; Spar, B.; Weig, B. J. Med.
Chem. 2005, 48, 2274; (d) Guo, T.; Hunter, R. C.; Gu, H.
Z.; Rokosz, L. L.; Stauffer, T. M.; Hobbs, D. W. Bioorg.
Med. Chem. Lett. 2005, 15, 3696; (e) Guo, T.; Shao, Y. F.;
Qian, G.; Rokosz, L. L.; Stauffer, T. M.; Hunter, R. C.;
Babu, S. D.; Gu, H. Z.; Hobbs, D. W. Bioorg. Med. Chem.
Lett. 2005, 15, 3691; (f) Kanuma, K; Omodera, K.;
Nishiguchi, M.; Funakoshi, T.; Chaki, S.; Semple, G.;
Tran, T. A.; Kramer, B.; Hsu, D.; Casper, M.; Thomsen,
B.; Sekiguchi, Y. Bioorg. Med. Chem. Lett. 2005, 15, 3853;
CN
F
Cl
N
H
N
N
H
N
R
Compound
R
MCH Ki (nM)
33a
33b
33c
33d
Boc
H
48
20
39
14
Cyclopentyl
Cyclopropylmethyl
a See Table 1 notes.