W. P. Blackaby et al. / Bioorg. Med. Chem. Lett. 16 (2006) 1175–1179
1179
uses displacement of [3H]Ro 15-1788 to measure the ex-
tent to which the compound penetrates the CNS and
occupies GABAA receptor benzodiazepine binding sites.
When dosed at 1 mg/kg po as a suspension in 0.5%
methocel, 11d gave 50% receptor occupancy with a plas-
ma Occ50 of 0.15 lM and brain to plasma ratio of 0.73.
G.; Macaulay, A.; Brown, N.; Howell, O.; Moore, K. W.;
Carling, R. W.; Street, L. J.; Castro, J. L.; Ragan, C. I.;
Dawson, G. R.; Whiting, P. J. Nat. Neurosci. 2000, 3, 587.
7. Atack, J. R. Expert Opin. Invest. Drugs 2005, 14, 601.
8. Teuber, L.; Watjen, F.; Fukuda, Y.; Ichimaru, Y.
WO Patent 99/19323, 1999.
9. Hallett, D. J.; Atack, J. R.; Castro, J. L.; Cook, S.;
Carling, R. W.; Dias, R.; Dawson, G. R.; Goodacre, S.;
Humphries, A.; Kelly, S.; Lincoln, R. J.; Marshall, G. R.;
McKernan, R. M.; Street, L. J.; Reynolds, D. S.; Russell,
M. G. N.; Smith, A.; Sheppard, W. F. A.; Stanley, J. L.;
Tye, S.; Wafford, K. A.; Whiting, P. J. Abstracts of Papers,
230th National Meeting of the American Chemical Soci-
ety, Washington, DC, 2005.
10. Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem.
1995, 60, 7508.
11. Blackaby, W. P.; Castro Pineiro, J. L.; Chambers, M. S.;
Goodacre, S. C.; Hallett, D. J.; Jones, P.; Lewis, R. T.;
MacLeod, A. M.; Maxey, R. J.; Moore, K. W.; Street, L.
J. WO Patent 02/076983, 2002.
In conclusion, the SAR of heterocyclic replacements for
the biaryl moiety of 2 has been investigated. Introducing
nitrogen into ring A of compound 2 has a profound ef-
fect on affinity, efficacy and metabolic stability. 6-Substi-
tuted pyridin-2-yls such as 3b–e showed reduced efficacy
at a3 receptors. Pyridines with the nitrogen at the 4-po-
sition such as 10b, 11c, and 11e showed higher efficacy at
a3 and functional selectivity over a1 receptors. Modifica-
tion of rings A and B in tandem enabled further modu-
lation of the efficacy profile which led to compound 11d
with high affinity at GABAA receptors and an attractive
efficacy profile, being an antagonist at a1b3c2 receptors
and a partial agonist at a3b3c2 receptors which exhibits
good receptor occupancy in the rat on oral dosing.
12. Abarbri, M.; Dehmel, F.; Knochel, P. Tetrahedron Lett.
1999, 40, 7449.
13. Guerret, P.; Jacquier, R.; Maury, G. Bull. Soc. Chim. Fr.
1972, 9, 3503.
14. Kubova, H.; Mikulecka, A.; Haugvicova, R.; Mares, P.
Naunyn-Schmiedeberg’s Arch. Pharmacol. 1999, 360,
565.
References and notes
1. Simon, J.; Wakimoto, H.; Fujita, N.; Lalande, M.;
Barnard, E. A. J. Biol. Chem. 2004, 279, 41422.
2. Sieghart, W. Pharmacol. Rev. 1995, 47, 181.
3. Bowery, G., Enna, S. J.; The GABA Receptors, 2nd ed.;
1997; p 332.
4. Gupta, S. P. Prog. Drug Res. 1995, 45, 67.
5. Atack, J. R. Curr. Drug Targets CNS Neurol. Disord.
2003, 2, 213.
15. Hadingham, K. L.; Wingrove, P.; Le Bourdelles, B.;
Palmer, K. J.; Ragan, C. I.; Whiting, P. J. Mol. Pharma-
col. 1993, 43, 970.
16. Smith, A. J.; Alder, L.; Silk, J.; Adkins, C.; Fletcher, A. E.;
Scales, T.; Kerby, J.; Marshall, G.; Wafford, K. A.;
Mckernan, R. M.; Atack, J. R. Mol. Pharmacol. 2001, 59,
1108.
17. Brown, N.; Kerby, J.; Bonnert, T. P.; Whiting, P. J.;
Wafford, K. A. Br. J. Pharmacol. 2002, 136, 965.
18. Cruskie, M. P., Jr.; Zoltewicz, J. A.; Abboud, K. A.
J. Org. Chem. 1995, 60, 7491.
6. McKernan, R. M.; Rosahl, T. W.; Reynolds, D. S.; Sur,
C.; Wafford, K. A.; Atack, J. R.; Farrar, S.; Myers, J.;
Cook, G.; Ferris, P.; Garrett, L.; Bristow, L.; Marshall,