R. M. Rodríguez Sarmiento et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4495–4500
4499
Table 3
Quinoline series. Lipophilicity and amphiphilicity calculated by DDGAM
O
N
1
R
R
R
O
Compound
hH3 Ki (nM)
R1
R
KOW_Clog P
pKa
DDGAM (kJ/mol)
À9.4
N
N
16
300
4.47
9.7
N
17
18
125
238
1.53
2.18
9.5
9.5
À5.06
À3.2
N
O
O
N
N
N
19
20
119
62
2.84
2.09
9.4
9.5
À5.4
À4.7
N
N
N
N
N
21
22
87
30
2.24
2.5
9.5
À3.21
À3.4
N
H
8.97
O
N
N
H
9. Threlfell, S.; Cragg, S. J.; Kallo, I.; Tur, G. F.; Coen, C. W.; Greenfield, S. A. J.
Neurosci. 2004, 24, 8704.
Acknowledgments
10. (a) Fox, G. B.; Esbenshade, T. A.; Pan, J. B.; Radex, R. J.; Krueger, K. M.; Yao, B. B. J.
Pharmacol. Exp. Ther. 2005, 313, 176; (b) Ligneau, X.; Perrin, D.; Landais, L.;
Camelin, J. C.; Calmels, T. P. G.; Berrebi, B. I. J. Pharmacol. Exp. Ther. 2007, 320,
320.
11. (a) Esbenshade, T. A.; Browman, K. E.; Bitner, R. S.; Strakhova, M.; Cowart, M.
D.; Brioni, J. D. Br. J. Pharmacol. 2008, 154, 1; (b) Celanire, S.; Wijtmans, M.;
Talaga, P.; Leurs, R.; de Esch, I. J. Drug Discovery Today 2005, 10, 1613; (c)
Esbenshade, T. A.; Fox, G. B.; Cowart, M. D. Mol. Interventions 2006, 6, 77; (d)
Passani, M. B.; Lin, J. S.; Hancock, A.; Crochet, S.; Blandina, P. Trends Pharmacol.
Sci. 2004, 25, 618; (e) For most recent development status please check:
12. (a) Ishizuka, T.; Hatano, K.; Murotani, T.; Yamatodani, A. Behav. Brain Res. 2008,
188, 250; (b) Masaki, T.; Yoshimatsu, H. Mini-Rev. Med. Chem. 2007, 7, 821; (c)
Hancock, A. A.; Brune, M. E. Expert Opin. Invest. Drugs 2005, 14, 223.
13. Roche, O.; Rodriguez-Sarmiento, R. M. Bioorg. Med. Chem. Lett. 2007, 17, 3670.
14. Roche, O.; Nettekoven, M.; Vivian, W.; Rodriguez-Sarmiento, R. M. Bioorg. Med.
Chem. Lett. 2008, 18, 4377.
15. Solubility measurements were performed by a method developed in house
from a 10 mM DMSO stock solution. This method is similar to the classical
thermodynamic shake-flask solubility, with the only difference being that
DMSO is removed before measurement by an additional lyophilization step.
The assay is called lyophilizated solubility assay (LYSA).
16. Measurements were performed according to Kansy, M.; Senner, F.; Gubernator,
K. J. Med. Chem. 1998, 41, 1007.
17. Measurements were performed according to Obach, R. S.; Baxter, J. G.; Liston, T.
E.; Silber, B. M.; Jones, B. C.; MacIntyre, F.; Rance, D. J.; Wastall, P. J. Pharm. Exp.
Ther. 1997, 283, 46.
18. Genotoxicity is estimated with the use of the AMES microsuspension assay,
where the read-out parameter is the increase in the number of revertant
colonies (mutation frequency) of treated compared to untreated control in five
different Salmonella typhimurium tester strains.The micronucleus in vitro test
(MNT in vitro test) is used to detect chromosomal damage. The read-out
It is with real pleasure that we wish to thank all our collabora-
tors whose contributions made the work described possible and so
enjoyable, especially Susanne Raab and Christoph Ullmer. Also spe-
cial thanks to Dr. Holger Fischer for his valuable comments.
References and notes
1. (a) Parsons, M. E.; Ganellin, C. R. Br. J. Pharmacol. 2006, 147, S127; (b) Hough, L.
B. Mol. Pharmacol. 2001, 59, 415.
2. (a) Hill, S. J.; Ganellin, C. R.; Timmermann, H.; Schwartz, J. C.; Shankley, N. P.;
Young, J. M.; Schunack, W.; Levi, R.; Haas, H. L. Pharmacol. Rev. 1997, 49, 253;
(b) Leurs, R.; Church, M. K.; Taglialatela, M. Clin. Exp. Allergy 2002, 32, 489; (c)
Ganellin, C. R. J. Med. Chem. 1981, 24, 913; (e) Schunack, W. J. Int. Med. Res.
1989, 17, 9A.
3. (a) Zhang, M.; Thurmond, R. L.; Dunford, P. J. Pharmacol. Therap. 2007, 113, 594;
(b) De Esch, I. J. P.; Thurmond, R. L.; Jongejan, A.; Leurs, R. Trends Pharmacol. Sci.
2005, 26, 462; (c) Jablonowski, J. A.; Carruthers, N. I.; Thurmond, R. L. Mini-Rev.
Med. Chem. 2004, 4, 993.
4. Arrang, J. M.; Garbarg, M.; Schwartz, J. C. Nature 1983, 302, 832.
5. Arrang, J. M.; Garbarg, M.; Schwartz, J. C. Neuroscience 1987, 23, 149.
6. (a) Schlicker, E.; Kathmann, M. In The Histamine H3 Receptor; A Target for New
Drugs; Leurs, R., Timmermann, H., Eds., 1st Ed.; Elservier Science B.V.:
Amsterdam, 1998; pp 13–26; (b) Leurs, R.; Blandina, P.; Tedford, C.;
Timmermann, H. Trends Pharmacol. Sci. 1998, 19, 177.
7. Blandina, P.; Giorgett, M.; Bartoli, L.; Cecchi, M.; Timmermann, H.; Leurs, R. Br. J.
Pharmacol. 1996, 119, 1656.
8. (a) Di Carlo, G.; Ghi, P.; Orsetti, M. Prog. Neuropsychopharmacol. Biol. Psychiatry
2000, 24, 275; (b) Medhurst, A. D.; Atkins, A. R.; Beresford, I. J.;
Brackenborough, K.; Briggs, M. A.; Calver, A. R. J. Pharmacol. Exp. Ther. 2007,
321, 1032.