11. Keenan, R. T.; Schlesinger, N. Curr. Rheumatol. Rep. 2016,
18, 32
clearance (T1/2, 19.8 h) among 9a, 9b, 16i and 19b by oral dose
of 10 mg/kg.
12. Miner, J.N.; Tan, P. Ann. Rheum. Dis. 2012, 71(suppl 2),
446.
13. Ouk, S.; Gunic, E.; Vernier, J. US 20130281469.
14. Li-Tain, Y.; Barry D, Q. WO 2013067425.
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Table 4
Pharmacokinetic properties of compounds 9a, 9b, 16i, and 19b
Parameters
Rat(PO)
Rat(IV)
16i
9a
10
9b
16i
10
19b
10
9a
9b
19b
Dose (mg/kg)
Tmax (h)
10
1
1
1
1
1
17. O’Neil, J.D.; Bamat, M.; Von Borstel, R.; Sharma, S.;
Arudchandran, R. WO 2009151695.
18. Wempe, M.F.; Jutabha, P.; Quade, B.; Iwen, T.J.; Frick,
M.M.; Ross, I.R.; Rice, P.J.; Anzai, N.; Endou, H. J. Med.
Chem. 2011, 54, 2701.
19. Wempe, M. F.; Quade, B.; Jutabha, P.; Iwen, T.; Frick, M.;
Rice,P.J.; Wakui, S.; Endou, H. Nucleos.Nucleot.Nucl. 2011,
30, 1312.
20. Wempe, M.F.; Lightner, J.W.; Miller, B.; Iwen, T.J.; Wakui,
S.; Anzai, N.; Jutabha, P.; Endou, H. Drug. Des. Dev. Ther.
2012, 6, 323.
1
2
5.3
0.9
3.9
5.7
6.5
2.7
2.5
0.4
ND
0.9
10.8
8.1
0.9
4.4
2.6
2.4
1.9
6.8
0.8
ND
0.9
T1/2 (h)
3.2
17.4
38.6
3.3
NDa
ND
59
19.6
9.0
4.1
0.3
6.4
5.2
ND
ND
27
19.8
10.5
181
28.7
ND
ND
28
14
7.7
64
Cmax (µg/ml)
AUC0-t (µg·h/ml)
MRT (h)
72.1
27.2
ND
ND
21.8
33.1
13.8
0.3
19
Cl (ml/min/kg)
Vss (L/kg)
F (%)
0.2
0.2
ND
0.3
21. Meanwell, N.A. J. Med. Chem. 2011, 54, 2529.
ND
a ND: No Data
In summary, we found that the sulfonamide could be utilized
to improve or maintain the hURAT1 inhibition activity by the
bioisosteric replacement of carboxylic group. Especially,
triflourosulfonamide 9b, 16i, and 19b exhibited excellent in vitro
inhibition activity. Through pharmacokinetic studies of
compounds 9a, 9b, 16i and 19b, we found that 9b and 19b
showed moderate pharmacokinetic profile.
Acknowledgment
We thank Kexin Xu, Ke Chen, and Shaohua Zhang of Hinova
Pharmaceuticals Inc who had contributed to this work. We also
thank Dr. Wu Du for suggestions to this work.
Supplementary data
Supplementary data (experimental procedures and biological
measuring methods) associated with this article can be found.
Reference and notes
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