4240
F. Giordanetto et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4232–4241
Blackburn, C., et al. 230th American Chemical Society
National Meeting, Washington, DC, USA, 2005: MEDI-
086; (f) Souers, A. J.; Gao, J.; Wodka, D.; Judd, A. S.;
Mulhern, M. M.; Napier, J. J.; Brune, M. E.; Bush, E. N.;
Brodjian, S. J.; Dayton, B. D.; Shapiro, R.; Hernandez, L.
E.; Marsh, K. C.; Sham, H. L.; Collins, C. A.; Kym, P. R.
Bioorg. Med. Chem. Lett. 2005, 15, 2752.
diamine spacer identified (1S,3S)-cyclohexane-1,3-di-
amine and (1S,3S)-cyclopentane-1,3-diamine as the best
scaffolds. Subsequent optimization of the substitution
pattern on the quinoline ring afforded 33
(IC50 = 0.1 nM, GTPcS IC50 = 1 nM), the most active
MCH-R1 antagonist in the present study. Systematic
structural exploration aimed at replacing thiophene
identified 51 as a novel, potent, and metabolically stable
MCH-R1 antagonist. Unfortunately, lack of efficacy in
the DIO model, at therapeutically meaningful doses,
precluded advancement of any member of this lead
series into further development.
10. Vasudevan, A.; Wodka, D.; Verzal, M. K.; Souers,
A. J.; Gao, J.; Brodjian, S.; Fry, D.; Dayton, B.;
Marsh, K. C.; Hernandez, L. E.; Ogiela, C. A.;
Collins, C. A.; Kym, P. R. Bioorg. Med. Chem. Lett.
2004, 14, 4879.
11. Arienzo, R.; Clark, D. E.; Cramp, S.; Daly, S.; Dyke, H.
J.; Lockey, P.; Norman, D.; Roach, A. G.; Stuttle, K.;
Tomlinson, M.; Wong, M.; Wren, S. P. Bioorg. Med.
Chem. Lett. 2004, 14, 4099.
12. Ulven, T.; Little, P. B.; Receveur, J.; Frimurer, T. M.;
Rist, Ø.; Nørregaard, P. K.; Ho¨gberg, T. Bioorg. Med.
Chem. Lett. 2006, 16, 1070.
13. Jiang, J.; Hoang, M.; Young, J. R.; Chaung, D.; Eid, R.;
Turner, C.; Lin, P.; Tong, X.; Wang, J.; Tan, C., et al.
Bioorg. Med. Chem. Lett. 2006, 16, 5270.
Acknowledgments
The authors thank their AstraZeneca coworkers Mia
´
Boethius-Litzen, Susanne Ekehed, Mikael Rehngren,
and Arja Schedwin for providing MCH-R1 binding
and functional data, human CLint data, and
in vivo PK data, respectively, as well as Pernilla
˚
Hakansson for running the mouse diet-induced obes-
ity model.
14. Clark, D. E.; Higgs, C.; Wren, S. P.; Dyke, H. J.; Wong,
M.; Norman, D.; Lockey, P. M.; Roach, A. G. J. Med.
Chem. 2004, 47, 3962.
15. Ulven, T.; Frimurer, T. M.; Receveur, J.; Little, P. B.;
Rist, Ø.; Nørregaard, P. K.; Ho¨gberg, T. J. Med. Chem.
2005, 48, 5684.
References and notes
16. Giordanetto, F.; Lindberg, J.; Karlsson, O.; Inghardt, T.
Abstract of Papers, 232nd National Meeting of the
American Chemical Society, San Francisco, CA, 2006,
COMP-410.
17. Macdonald, D.; Murgolo, N.; Zhang, R.; Durkin, J. P.;
Yao, X.; Strader, C. D.; Graziano, M. P. Mol. Pharmacol.
2000, 58, 217.
1. Bittencourt, J. C.; Presse, F.; Arias, C.; Peto, C.; Vaughan,
J.; Nahon, J. L.; Vale, W.; Sawchenko, P. E. J. Comp.
Neurol. 1992, 319, 218.
2. Skofitsch, G.; Jacobowitz, D. M.; Zamir, N. Brain Res.
Bull. 1985, 15, 635.
3. Saito, Y.; Nothacker, H.-P.; Civelli, O. Trends Endocrinol.
Metab. 2000, 11, 299.
4. Schwartz, M. W.; Woods, S. C.; Porte, D.; Selley, R. J.;
Baskin, D. G. Nature 2000, 404, 661.
5. Qu, D.; Ludwig, D. S.; Grammeltoft, S.; Piper, M.;
Pelleymounter, M. A.; Cullen, M. J.; Mathes, F. W.;
Przypek, J.; Kanerek, R.; Maratos-Flier, E. Nature 1996,
380, 243.
18. Three-dimensional alignments were carried out with
ROCS (OpenEye Scientific Software, 3600 Cerrillos Rd.,
Suite 1107, Santa Fe, NM 87507) using the Shape
Tanimoto function to quantify similarity. An in-house
pharmacophore search method19 was employed to identify
central linkers that satisfied the three pharmacophoric
features described (N+, Hy1, and Hy2) within a root
˚
mean square deviation of 0.75 A.
6. Gomori, A.; Ishiara, A.; Ito, M.; Mashiko, S.; Matsuhita,
H.; Yumoto, M.; Ito, M.; Tanaka, T.; Tokita, S.; Moriya,
M.; Iwaasa, H.; Kanatani, A. Am. J. Physiol. Endocrinol.
Metab. 2003, 284, E583.
7. Ludwig, D. S.; Tritos, N. A.; Mastaitis, J. W.; Kulkarni,
R.; Kokkotou, E.; Elmiqst, J.; Lowell, B.; Flier, J. S.;
Maratos-Flier, E. J. Clin. Invest. 2001, 107, 379.
8. Shimada, M.; Tritos, N. A.; Lowell, B. A.; Flier, J. S.;
Maratos-Flier, E. Nature 1998, 396, 670.
9. (a) Takekawa, S.; Asami, A.; Ishihara, Y.; Terauchi, J.;
Kato, K.; Shimomura, Y.; Mori, M.; Murakoshi, H.;
Suzuki, N.; Nishimura, O.; Fujino, M. Eur. J. Pharmacol.
2002, 438, 129; (b) Borowsky, B.; Durkin, M. M.;
Ogozalek, K.; Marzabadi, M. R.; DeLeon, J.; Lagu, B.;
Heurich, R.; Lichtblau, H.; Shaposhnik, Z.; Daniewska,
I., et al. Nat. Med. 2002, 8, 825; (c) McBriar, M. D.;
Guzik, H.; Xu, R.; Paruchova, J.; Li, S.; Palani, A.;
Clader, J. W.; Greenlee, W. J.; Hawes, B. E.; Kowalski, T.
J.; O’Neill, K., et al. J. Med. Chem. 2005, 48, 2274; (d)
Handlon, A. L.; Al-Barazanji, K. A.; Barvian, K. K.;
Bighan, E. C.; Carlton, D. L.; Carpenter, A. J.; Cooper, J.
P.; Daniels, A. J.; Garrison, D. T.; Goetz, A. S., et al.
228th American Chemical Society National Meeting,
Philadelphia, PA, USA , 2004: MEDI-193; (e) Iyengar,
R.; Souers, A. J.; Lynch, J. K.; Judd, A. S.; Gao, J.;
Freeman, J. C.; Mulhern, M.; Vasudevan, A.; Wodka, D.;
19. Lyne, P. D.; Kenny, P. W.; Cosgrove, D. A.; Deng, C.;
Zabludoff, S.; Wendoloski, J. J.; Ashwell, S. J. Med.
Chem. 2004, 47, 1962.
20. The preparation of representative compounds is described
in: Ray, A. K.; Sigfridsson, E. M.; Linusson, A.; Stina,
M.; Sandberg, P. M.; Inghardt, T.; Svensson, A. M.;
Brickmann, K. WO2004/004726 (compound 9), and in:
Evertsson, E.; Inghardt, T.; Lindberg, J.; Linusson, A.;
Giordanetto, F. WO2005/066132 (compounds 13, 15, 23,
29, 31, 38, 41, 43, 49–55).
21. Dansette, P. M.; Thang, D. C.; El Amri, H.; Mansuy, D.
Biochem. Biophys. Res. Commun. 1992, 186, 1624.
22. A variety of structural descriptors, including logD and
aqueous solubility predictions, served to profile and filter
the chemical library. These were calculated using in-house
developed models implemented in Pipeline Pilot version.
4.5, SciTegic: San Diego, CA.
23. The preparation of tert-butyl[(1S,3S)-3-aminocyclopen-
tyl]carbamate is detailed in Evertsson, E.; Inghardt, T.;
Lindberg, J.; Linusson, A.; Giordanetto, F. WO2005/
066132.
24. Female C57Bl/6J mice were given ad libitum access to
calorie-dense ‘cafeteria’ diet (soft chocolate/cocoa-type
pastry, chocolate, fatty cheese, and nougat) and standard
lab chow for 8–10 weeks until a body weight of 45–50 g
was achieved. Compounds to be tested were then admin-