1380
B. R. Neustadt et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1376–1380
Table 3. Rat pharmacokinetic properties of SCH 420814 HCl salta
po dose
(mg/kg)
iv dose
(mg/kg)
Cmax po
(nM)
Tmax, po
(h)
AUC po
(nM h)
t1/2 iv
(h)
Cl, iv
(mL minꢀ1 kgꢀ1
Vss, iv
(L kgꢀ1
)
Fpo
(%)
)
3
1
762
0.25
1560
2.1
37
2.6
57
a Mean values, n = 3 per route.
Pratt, R. M.; Revell, D.; Upton, R.; Dourish, C. T.
Neurology 2003, 61 (Suppl. 6), S101.
volume of distribution (Vss), and a brain-to-plasma ratio
of 1. When administered to rats as the hydrochloride
salt, the compound was well absorbed, with a measured
oral bioavailability of 57%. In several species, a major
metabolite was the O-desmethyl compound.
6. (a) Baraldi, P. G.; Manfredini, S.; Simoni, D.; Zapaterrra,
L.; Zocchi, C.; Dionisotti, S.; Ongini, E. Bioorg. Med.
Chem. Lett. 1994, 4, 2539; (b) Baraldi, P. G.; Cacciari, B.;
Spalutto, G.; Villatoro, M. J. P.; Zocchi, C.; Dionisotti, S.;
Ongini, E. J. Med. Chem. 1996, 39, 1164; (c) Ongini, E.
Drug Dev. Res. 1997, 42, 63; (d) Baraldi, P. G.; Cacciari,
B.; Spalutto, G.; Bergonzoni, M.; Dionisotti, S.; Ongini,
E.; Varani, K.; Borea, P. A. J. Med. Chem. 1998, 41, 2126;
(e) Baraldi, P. G.; Fruttarolo, F.; Tabrizi, M. A.; Preti, D.;
Romagnoli, R.; El-Kashef, H.; Moorman, A.; Varani, K.;
Gessi, S.; Merighi, S. K.; Borea, P. A. J. Med. Chem. 2003,
46, 1229; (f) Baraldi, P. G.; Tabrizi, M. A.; Bovero, A.;
Avitabile, B.; Preti, D.; Fruttarolo, F.; Romagnoli, R.;
Varani, K.; Borea, P. A. Eur. J. Med. Chem. 2003, 38, 367.
7. This work was reported in part at the American Chemical
Society 231st National Meeting (March 2006), paper
MEDI 204.
In conclusion, novel, orally active phenylpiperazine
adenosine A2A receptor antagonists derived from SCH
58261 were identified, exemplified by SCH 412348. Opti-
mization of the phenylpiperazine substitution resulted in
identification of SCH 420814, which displays potent oral
anti-cataleptic activity and favorable pharmacokinetic
properties in rats. Further pharmacological character-
ization of SCH 412348 and SCH 420814 will be reported
in due course.
References and notes
8. Klo¨tzer, W.; Herberz, M. Monats. Chem. 1965, 96, 1567,
Also purchased from AstaTech, Inc.
9. El Ashry, E. S. H.; El Kilany, Y.; Rashed, N.; Assafir, H.
Adv. Heterocyclic Chem. 2000, 75, 79.
10. Professor Andrew McPhail, private communication.
11. Morita, S.; Kitano, K.; Matsubara, J.; Ohtani, T.;
Kawana, Y.; Otsubo, K.; Uchida, M. Tetrahedron 1998,
54, 4811.
12. A detailed description of the adenosine receptor binding
assays is provided in Bioorg. Med Chem. Lett. 2005, 15,
1333, footnote 11.
1. (a) Jacobson, K. A.; van Galen, P. J. M.; Williams, M.
J. Med. Chem. 1992, 35, 4007; (b) Muller, C. E. Drugs
of the Future 2000, 25, 1043; (c) Schwarzschild, M. A.;
Agnati, L.; Fuxe, K.; Chen, J-F.; Morelli, M. Trends
Neurosci. 2006, 29, 647.
2. (a) Bara-Himenez, W.; Sherzai, A.; Dimitrova, T.; Favit,
A.; Bibbiani, F.; Gillespie, M.; Morris, M. J.; Mouradian,
M. M.; Chase, T. N. Neurology 2003, 61, 293; (b) Hauser,
R. A.; Hubble, J. P.; Truong, D. D. Neurology 2003, 251,
297.
3. Francis, J. E.; Cash, W. D.; Psychoyos, S.; Ghai, G.;
Wenk, P.; Friedmann, R. C.; Atkins, C.; Warren, V.;
Furness, P.; Hyun, J. L.; Stone, G. A.; Desai, M.;
Williams, M. J. Med. Chem. 1988, 31, 1014.
13. (a) Myslobodsky, M. S.; Mintz, M.; Kofman, O. Phar-
macol. Biochem. Behav. 1981, 15, 93; (b) Pinna, A.;
Volpini, R.; Cristalli, G.; Morelli, M. Eur. J. Pharmacol.
2005, 512, 157.
4. Sarges, R.; Howard, H. R.; Brown, R. G.; Lebel, L. A.;
Seymour, P. A.; Koe, B. K. J. Med. Chem. 1990, 33, 2240.
5. For recent examples of bicyclic systems, see: (a) Vu, C. B.;
Pan, D.; Peng, B.; Sha, L.; Kumaravel, G.; Jin, X.;
Phadke, D.; Engber, T.; Huang, C.; Reilly, J.; Tam, S.;
Petter, R. C. Bioorg. Med. Chem. Lett. 2004, 14, 4831; (b)
Vu, C. B.; Shields, P.; Peng, B.; Kumaravel, G.; Jin, X.;
Phadke, D.; Wang, J.; Engber, T.; Ayyub, E.; Petter, R. C.
Bioorg. Med. Chem. Lett. 2004, 14, 4835; (c) Dowling, J.
E.; Vessels, J. T.; Haque, S.; Chang, H. X.; van Vloten, K.;
Kumaravel, G.; Engber, T.; Jin, X.; Phadke, D.; Wang, J.;
Ayyub, E.; Petter, R. C. Bioorg. Med. Chem. Lett. 2005,
15, 4809; (d) Weiss, S. M.; Benwell, K.; Cliffe, I. A.;
Gillespie, R. J.; Knight, A. R.; Lerpiniere, J.; Misra, A.;
14. Assay methodology described in: Ongini, E.; Dionosotti,
S.; Gessi, S.; Irenius, E.; Fredholm, B. B. Naunyn
Schmiederbergs Arch. Pharmacol. 1999, 359, 7.
15. Assay methodology described in: Jacobson, K. A.; Ji, X.
D. Drug Design Discov. 1999, 16, 217.
16. Includes adrenergic a1a, a1b, a2a, a2b, a2c, b1; NE uptake:
AT1 and 2; bradykinin B2; CGRP; CCK1 and 2; CB1 and
2; C5a; CCR2, 3, 6, and 7; CXCR3; dopamine uptake; ET-
A and B; FPR1; EGF; galanin and GALR2; glucagon;
H3; IL-6; LTB4 and D4; melanocortin; motilin; musca-
rinic M1-M5; NK1-3; NPY1-5; prostaglandin EP1 and IP;
5-HT 1A, 2C, 6, and 7; progesterone; VIP; and V1 a.
17. A single measurement at pH 7.4 gave solubility below
10 ng/mL.