840
P. W. Smith et al. / Bioorg. Med. Chem. Lett. 19 (2009) 837–840
Table 5
Exposure data generated in gerbil cortex NK3 occupancy study
Compound
Calc logP
(measured logD7.4
Dose (mg/kg) NK3 pKi
route
Mean total brain
ng/ml (nM)
Measured tissue binding % Free brain
Measured mean receptor
occupancy (RO) %
)
gerbil31
gerbil brain
conc (nM)
GSK172981 10
GSK256471 20
SB223412
(talnetant, 2)
SB236984
6.8
4.5 (3.2)
7.4
30 ip
10 po
10 po
30 po
10 po
30 po
8.3
8.9
7.7
2062 (5011)
61 (118)
9 (24)
42 (110)
6 (10)
99.3
96.7
98.8
35
4
0.3
1.3
0.02
0.03
61
60
6
27
12
40
5.9
8.7
99.8
(osanetant, 1)
10 (16)
Rigby, M.; Royo, I.; Russell, M. G.; Sohal, B.; Tsao, K. L.; Williams, B. Bioorg. Med.
Chem. Lett. 2006, 16, 5748.
17. Yan, H.; Kerns, J.; Jin, Q., et al Synthetic Commun. 2005, 35, 3105.
18. Smith, P. W.; Dawson, L. A. Recent Patents CNS Drug Discov. 2008, 3,
1.
and receptor affinity are considered rather than total brain concen-
tration (Table 5). Equilibrium dialysis measurement of the brain
tissue binding of 10, perhaps unsurprisingly, revealed very high
non-specific binding and a very low proportion of unbound drug
(Fub 0.7%).33,34 Compound 20, with reduced lipophilicity, has an in-
creased proportion of free drug (Fub 3.3%, ꢀ5-fold higher than 10).
This difference, together with higher affinity for the NK3 receptor,
offsets the fact that the total brain concentration of 20 is much
19. Meltzer, H. Drug Discov. Today 2006, 3, 555.
20. Albert, J.; Potts, W. Expert Opin. Ther. Patents 2006, 16, 925.
21. Rumsey, W.; Kerns, J. K. Handbook Exp. Pharmacol. 2004, 164, 273.
22. Blaney, F. E.; Raveglia, L. F.; Artico, M.; Cavagnera, S.; Dartois, C.; Farina, C.;
Grugni, M.; Gagliardi, S.; Luttmann, M. A.; Martinelli, M.; Nadler, G. M.; Parini,
C.; Petrillo, P.; Sarau, H. M.; Scheideler, M. A.; Hay, D. W.; Giardina, G. A. J. Med.
Chem. 2001, 44, 1675.
lower than 10 (118 nM vs 5 lM).
In light of the excellent brain receptor occupancy profiles of 10
and 20, these compounds have been progressed for further in vivo
evaluation which will be reported in due course.35
23. Giardina, G. A.; Artico, M.; Cavagnera, S.; Cerri, A.; Consolandi, E.; Gagliardi, S.;
Graziani, D.; Grugni, M.; Hay, D. W.; Luttmann, M. A.; Mena, R.; Raveglia, L. F.;
Rigolio, R.; Sarau, H. M.; Schmidt, D. B.; Zanoni, G.; Farina, C. Farmaco 1999, 54,
364.
In summary, new SAR studies within the established quinoline
series of NK3 receptor antagonists has led to the discovery of two
promising new compounds which both produce excellent NK3
receptor occupancy in gerbil brain.
24. Giardina, G. A.; Raveglia, L. F.; Grugni, M.; Sarau, H. M.; Farina, C.; Medhurst, A.
D.; Graziani, D.; Schmidt, D. B.; Rigolio, R.; Luttmann, M.; Cavagnera, S.; Foley, J.
J.; Vecchietti, V.; Hay, D. W. J. Med. Chem. 1999, 42, 1053.
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