6632
J. N. Hemenway et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6629–6632
Glutathione activity is known to be high in red blood cells
and tissues such as the liver and kidney of rats and
humans. The rapid and complete conversion of 4 to
CBZ in rat whole blood is consistent with the proposed
mechanism of conversion via reaction with glutathione.
7.33–7.42 (m, 2H), 7.45–7.50 (m, 6H), 7.81 (br s, 3H). The
addition of two drops of D O to the NMR sample resulted
in the disappearance of the peaks at 7.06 and 7.81. HRMS
2
1
4
+
+
(TOF ES ) m/z calcd C17
found 312.1155.
18 3
H N OS (M+H) 312.1171,
1
0. Martin, A. N.; Swarbrick, J.; Cammarata, A. Physical
Pharmacy: Physical Chemical Principles in the Pharma-
ceutical Sciences, 3rd ed., 1985; 194 pp.
References and notes
1
1. Yoshioka, S.; Stella, V. J. Stability of Drugs and Dosage
Forms; Kluwer Academic/Plenum Publishers: New York,
1
. (a) Levy, R. H.; Mattson, R. H.; Meldrum, B. S.,
Antiepileptic Drugs, 4th ed., 1995; 1120 pp; (b) Loiseau,
P.; Duche, B.; Pedespan, J. M. Epilepsia 1985, 36, 1182.
. Pellock, J. M. Epilepsia 1987, 28, S64.
2
000, pp 63–64.
2. Remmel, R. P.; Sinz, M. W.; Cloyd, J. C. Pharm. Res.
990, 7, 513.
3. Animal studies. Adult male Sprague–Dawley rats (200–
27 g) were purchased from Harlan (Indianapolis, IN)
1
1
1
2
3
. (a) Chen, X.-Q.; Venkatesh, S. Pharm. Res. 2004, 21, 1758;
2
(b) Brewster, M. E.; Anderson, W. R.; Estes, K. S.; Bodor,
N. J. Pharm. Sci. 1991, 80, 380.
with jugular and carotid artery pre-cannulated. Rats were
attached to a swivel device allowing the rat free mobility
and access to water during dosing and blood sampling
experiments, but fasted for 12 h prior to dosing. A
4
. (a) Wehnert, H. U. German patent 3,813,015, 1989; (b)
Tauboll, E.; Lindstrom, S.; Klem, W.; Gjerstad, L. A.
Epilepsy Res. 1990, 7, 59; (c) Brewster, M. E.; Anderson,
W. R.; Estes, K. S.; Bodor, N. J. Pharm. Sci. 1991, 80,
ꢀ1
1
3.58 mg kg
CBZ control dose solubilized with 10%
HP-b-CD in sterile saline followed by an equivalent dose
3
80; (d) Loescher, W.; Hoenack, D.; Richter, A.; Schulz,
ꢀ
1
of 4 (24.30 mg kg ) in sterile saline (or vice versa) were
administered intravenously in a crossover design following
a 48-h washout period. Each dose was prepared in excess
to provide the specified dose of 1 or 4 in a volume of
H.-U.; Schuerer, M., et al. Epilepsia 1995, 36, 255; (e)
Loescher, W.; Hoenack, D. Epilepsia 1997, 38, 106.
. (a) Yalkowsky, S. H.; Krzyzaniak, J. F.; Ward, G. H.
J. Pharm. Sci. 1998, 87, 787; (b) Yalkowsky, S. H.;
Valvani, S. C. Drug Intell. Clin. Pharm. 1977, 11, 417.
. Guarino, V. R.; Stella, V. J. In Prodrugs: Challenges and
Rewards, Part 2; Stella, V. J., Borchardt, R. T., Hageman,
M. J., Oliyai, R., Maag, H., Tilley, J. W., Eds.; Springer:
New York, 2007; pp 133–187.
5
6
1
.00 mL. Dosing syringes and needles were completely
filled and the 1.00- mL dose was administered as indicated
by the change in position of the syringe plug. Doses were
given iv through the jugular vein cannula as a bolus dose
over 1 min. Blood samples were collected manually. Blood
(
1
200 lL) was drawn from the carotid artery cannula at 2,
5, 30, 60, 120, 240, 360, and 480 min post-dose. Excess
7
. (a) Guarino, V. R.; Karunaratne, V.; Stella, V. J. Bioorg.
Med. Chem. Lett. 2007, 17, 4910; (b) Guarino, V. R. Ph.D.
Dissertation; University of Kansas, May 2004; (c) Gua-
rino, V. R.; Karunaratne, V.; Stella, V. J. PCT Int. Appl.
blood was returned and 200 lL of normal saline was
infused into the jugular vein cannula following each blood
sample to replace lost blood volume. A volume of
heparinized saline (100 UI mL ) equivalent to the can-
nula volume was infused into the cannula to create a
heparin lock after replacing the lost blood volume. Drawn
blood samples were immediately added to a solution of
032908, 2003.
ꢀ1
8
. (a) Harpp, D. N.; Steliou, K.; Chan, T. H. J. Am. Chem.
Soc. 1978, 100, 1222; (b) Klose, J.; Reese, C. B.; Song, Q.
Tetrahedron 1997, 53, 14411.
1
9
. N-(phenylthio)CBZ (2). H NMR (400 MHz, CDCl ) d
3
0
.10 M N-methylmaleimide and 1.0 M acetic acid in
5
3
2
.76 (s, 1H), 6.97 (s, 2H), 7.16–7.27 (m, 2H), 7.28–7.34 (m,
H), 7.34–7.44 (m, 4H), 7.45–7.51 (m, 2H), 7.52–7.57 (m,
H).
methanol (1–10 parts blood) and vortexed. Processed
samples were stored at 4 ꢁC until analyzed.
1
1
4. (a) Erat, M.; Sakiroglu, H.; Ciftci, M. J. Enzyme Inhib.
Med. Chem. 2005, 20, 69; (b) Suzuki, T.; Agar, N. S.;
Suzuki, M. Comp. Biochem. Physiol. B, Biochem. Mol.
Biol. 1984, 79, 515; (c) Baars, A. J.; Mukhtar, H.;
Zoetemelk, C. E. M.; Jansen, M.; Breimer, D. D. Comp.
Biochem. Physiol. C, Comp. Pharmacol. 1981, 70, 285.
N-(OEt-Cys)-CBZ (3). H NMR (400 MHz, DMSO-d ) d
6
1
4
7
.15 (t, 3H), 2.22–2.36 (m, 1H), 3.03–3.14 (m, 1H), 4.00–
.08 (m, 1H), 4.16 (q, 2H), 6.97 (s, 2H), 7.09 (s, 1H), 7.31–
.38 (m, 2H), 7.39–7.45 (br m, 6H), 8.41 (br s, 3H).
1
N-cysteamine-CBZ (4). H NMR (400 MHz, DMSO-d6) d
2.74 (t, 2H), 2.89 (q, 2H), 7.02 (s, 2H), 7.06 (s, 1H)