4554
Y. Xiang et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4550–4554
Table 4
In vitro ADME data for selected SK1 inhibitors
g
g
g
g
g
Compound Sol., pH
7.4a
PAMPA pH
6.5–7.4b
c log Pc log Dd Microsomes rat Microsomes
1A2 IC50
M)
2C9 IC50
M)
2C19 IC50
M)
2D6 IC50
M)
3A4 IC50
M)
e
f
CLint
human CLint
(
l
(
l
(
l
(
l
(l
7
51
53
54
27
>74
>75
13
46
49
58
44
3.0
2.7
3.3
3.8
3.7
2.9
3.6
4.3
60
45
12
<4.5
10
>5.0
>5.0
>5.0
>5.0
>5.0
>5.0
>5.0
>5.0
>5.0
1.4
>5.0
1.2
>5.0
>5.0
>5.0
>5.0
>5.0
>5.0
4.3
49.5
50.2
38.8
N/Ah
a
b
c
Solubility measurement determined from DMSO stock at pH 7.4 in phosphate buffered saline, recorded as lg/mL.
PAMPA (parallel artificial membrane permeability assay), pION Inc. Double Sink Method using donor (pH 6.5) and acceptor (pH 7.4 sink buffer) reported as 10–6 cm/s.
c log P calculated log P (octanol–water partition coefficient).
log D distribution coefficient measured at pH 7.4.
d
e
f
Metabolic stability in rat liver microsomes. Intrinsic clearance reported as
lL/min/mg protein.
Metabolic stability in human liver microsomes. Intrinsic clearance reported as
lL/min/mg protein.
g
h
Cytochrome P450 inhibition using cDNA expressed isozymes and fluorescent probe substrates, reported as
lM.
Data not available.
Table 5
Rat PK data for selected SK1 inhibitors
b
c
e
f
Compound
Dose
AUCa (ng h/mL)
t1/2 (h)
Cmax (ng/mL)
CLd (mL/min/kg)
81.8
Vdss (mL/kg)
Tmax (h)
Fg (%)
54
54
51
51
1 mg/kg (iv)
3 mg/kg (po)
1 mg/kg (iv)
3 mg/kg (po)
204
94.8
439
232
1.64
1.64
4.30
7.55
7860
5550
37.5
82.5
0.75
0.33
15.3
17.6
37.1
a
b
c
d
e
f
Area under the plasma concentration versus time curve after drug administration.
Half-life (time required for the plasma concentration to be reduced by 50%).
Maximum plasma concentration observed after drug administration.
Clearance (the volume of plasma from which the drug is completely removed per unit time).
Volume of distribution at steady state.
Time required to reach maximum concentration.
Oral bioavailability.
g
6. Tara, T. A.; Hannun, Y. A.; Obeid, L. M. J. Biochem. Mol. Biol. 2006, 39,
113.
References and notes
7. Li, Z.; Chen, W.; Hale, J. J.; Lynch, C. L.; Mills, S. G.; Hajdu, R.; Keohane, C. A.;
Rosenbach, M. J.; Milligan, J. A.; Shei, G.-J.; Chrebet, G.; Parent, S. A.; Bergstrom,
J.; Card, D.; Forrest, M.; Quackenbush, E. J.; Wickham, L. A.; Vargas, H.; Evans, R.
M.; Rosen, H.; Mandala, S. J. Med. Chem. 2005, 48, 6169.
8. Chiou, S.; Shine, H. J. J. Heterocycl. Chem. 1989, 26, 125.
9. Lin, Y.; Hlavka, J. J.; Bitha, P.; Lang, S. A. J. Heterocycl. Chem. 1983, 20,
1693.
10. Brown, P.; Best, D. J.; Broom, N. J. P.; Cassels, R.; O’Hanlon, P. J.; Mitchell, T. J.;
Osborne, N. F.; Wilson, J. M. J. Med. Chem. 1997, 40, 2563.
11. Andersen, J.; Bolvig, S.; Liang, X. Synlett 2005, 2941.
12. Wiley, R. H.; England, D. C.; Behr, L. C. In Organic Reactions; Adams, R., Ed.;
Wiley & Sons: New York, 1951; p 367.
13. Baddar, F. G.; Al-Hajjar, F. H.; El-Rayyes, N. R. J. Heterocycl. Chem. 1976, 13,
257.
14. The IC50s were determination based on a method described in Ref. 1. All the
values of IC50s are the average of at least two times determinations.
15. Chan, W. N.; Smith, P. W.; Wyman, P. A. WO 2005/014575, 2005.
1. Part I is the publication: Xiang, Y.; Asmussen, G.; Booker, M.; Hirth, B.; Kane, J.
L., Jr.; Liao, J.; Noson, K. D.; Yee, C. Bioorg. Med. Chem. Lett. 2009, 19, 6119.
2. De Jonghe, S.; Van Overmeire, I.; Poulton, S.; Hendrix, C.; Busson, R.; Van
Calenbergh, S.; De Keukeleire, D.; Spiegel, S.; Herdewijn, P. Bioorg. Med. Chem.
Lett. 1999, 9, 3175.
3. (a) Kohama, T.; Olivera, A.; Edsall, L.; Nagiec, M. M.; Dickson, R.; Spiegel, S. J.
Biol. Chem. 1998, 273, 23722; (b) Melendez, A. J.; Carlos-Dias, E.; Gosink, M.;
Allen, J. M.; Takacs, L. Gene 2000, 251, 19.
4. (a) Xia, P.; Wang, L.; Moretti, P. A.; Albanese, N.; Chai, F.; Pitson, S. M.; D’Andrea,
R. J.; Gamble, J. R.; Vadas, M. A. J. Biol. Chem. 2002, 277, 7996; (b) Bonhuure, E.;
Pchejetski, D.; Aouali, N.; Morjani, H.; Levade, T.; Kohama, T.; Cuvillier, O.
Leukemia 2002, 20, 95.
5. (a) Maceyka, M.; Sankala, H.; Hait, N. C.; Stunff, H. L.; Liu, H.; Toman, R.; Collier,
C.; Zhang, M.; Satin, L. S.; Merrill, A. H.; Milstien, S., Jr.; Spiegel, S. J. Biol. Chem.
2005, 280, 37118; (b) Okada, T.; Ding, G.; Sonoda, H.; Kajimoto, T.; Haga, Y.;
Khosrowbeygi, A.; Gao, S.; Miwa, N.; Jahangeer, S.; Nakamura, S. J. Biol. Chem.
2005, 280, 36318.