Table 3. Mouse NaV activities, PK parameters and in vivo efficacy of selected compounds
Writhing
ED50
(mg/kg)
Locomotor
activity ID50
(mg/kg)
PB freeb
(%)
Cmax
(ng/mL)
AUC
Mouse NaV1.1
Mouse NaV1.7
Cmpd
IC50a (M)
IC50a (M)
Tmax (hr)
(hr•ng/mL)
II
21
11
NTc
NTc
1.99
NTc
5.55
4.18
NTc
NTc
16d
NTc
21
45
2h
9a
9d
9lf
9o
3.1
0.69
34
1.2
0.50d
0.50d
0.50e
0.50g
0.50g
18d
NTc
NTc
7.0
10
NTc
NTc
20
0.96
4.8
169d
467e
445g
161g
525d
692e
1906g
303g
0.67
2.4
0.79
1.3
NDh
19
111
aValues in an inactivated state. bUnbound fractions (%) in mouse plasma. cNot tested. dAverage of three CD mice dosed at 30 mg/kg
p.o. in N,N-dimethylacetamide/Tween 80/saline: 10/10/80. eAverage of three CD mice dosed at 30 mg/kg p.o. in 0.5% methylcellulose
f
g
suspension. Fumaric acid salt. Average of three db/db mice dosed at 30 mg/kg p.o. in N,N-dimethylacetamide/Tween 80/saline:
10/10/80. hNot determined.
In summary, the discovery and optimization of novel NaV1.7
inhibitors have been described. The replacement of
behavior in a dose-dependent manner, with ED50 = 19 mg/kg, and
exhibited an expanded CNS safety margin. This biological
profile is superior to that of the currently used drug, mexiletine.
The optical resolution of compound 9o, followed by the
evaluation of adverse cardiac effects is underway and will be
reported in the near future.
a
benzoxazinone moiety with an isoindolinone ring resulted in the
improvement of NaV1.5 selectivity, while the replacement of
piperazine with piperidine led to the enhancement of three human
NaV activities. In the modification of the right-hand side of the
phenyl ring, 4-substitution increased three human NaV activities,
while 2-methoxy substitution increased NaV1.5 selectivity. These
findings led to the identification of 2,4-substituted compound 9o
with potent human and mouse NaV1.7 inhibitory activities, as
well as fair NaV1.5 selectivity. Compound 9o reduced writhing
Acknowledgements
The authors would like to thank Ms. Chie Fujiwara for her
support in performing in vitro assays.
1.
Cox, J. J.; Reimann, F.; Nicholas, A. K.; Thornton, G.; Roberts, E.; Springell, K.; Karbani, G.; Jafri, H.; Mannan, J.; Raashid, Y.; Al-Gazali, L.;
Hamamy, H.; Valente, E. M.; Gorman, S.; Williams, R.; McHale, D. P.; Wood, J. N.; Gribble, F. M.; Woods, C. G. Nature 2006, 444, 894.
Drenth, J. P. H.; Waxman, S. G. J. Clin Invest. 2007, 117, 3603.
Minett, M. S.; Nassar, M. A.; Clark, A. K.; Passmore, G.; Dickenson, A. H.; Wang, F.; Malcangio, M.; Wood, J. N. Nature Commun. 2012, 3,
791.
2.
3.
4.
For recent articles on NaV1.7 inhibitors, see: (a) Lynch, S. M.; Tafesse, L.; Carlin, K.; Ghatak, P.; Kyle, D. J. Bioorg. Med. Chem. Lett. 2015, 25,
43. (b) Ho, G. D.; Tulshian, D.; Bercovici, A.; Tan, Z.; Hanisak, J.; Brumfield, S.; Matasi, J.; Heap, C. R.; Earley, W. G.; Courneya, B.; Herr, R.
J.; Zhou, X.; Bridal, T.; Rindgen, D.; Sorota, S.; Yang. S.-W. Bioorg. Med. Chem. Lett. 2014, 24, 4110. (c) Sun, S.; Jia, Q.; Zenova, A. Y.;
Chafeev, M.; Zhang, Z.; Lin, S.; Kwan, R.; Grimwood, M. E.; Chowdhury, S.; Young, C.; Cohen, C. J.; Oballa, R. M. Bioorg. Med. Chem. Lett.
2014, 24, 4397. (d) Hoyt, S. B.; London, C.; Abbadie, C.; Felix, J. P.; Garcia, M. L.; Jochnowitz, N.; Karanam, B. V.; Li, X.; Lyons, K. L.;
McGowan, E.; Priest, B. T.; Smith, M. M.; Warren, V. A.; Thomas-Fowlkes, B. S.; Kaczorowski, G. J.; Duffy, J. L. Bioorg. Med. Chem. Lett.
2013, 23, 3640. (e) Macsari, I.; Besidski, Y.; Csjernyik, G.; Nilsson, L. I.; Sandberg, L.; Yngve, U.; Åhlin, K.; Bueters, T.; Eriksson, A. B.; Lund,
P.-E.; Venyike, E.; Oerther, S.; Blakeman, K. H.; Luo, L.; Arvidsson, P. I. J. Med. Chem. 2012, 55, 6866. (f) Bregman, H.; Nguyen, H. N.; Feric,
E.; Ligutti, J.; Liu, D.; McDermott, J. S.; Wilenkin, B.; Zou, A.; Huang, L.; Li, X.; McDonough, S. I.; DiMauro, E. F. Bioorg. Med. Chem. Lett.
2012, 22, 2033. (g) Nguyen, H. N.; Bregman, H.; Buchanan, J. L.; Du, B.; Feric, E.; Huang, L.; Li, X.; Ligutti, J.; Liu, D.; Malmberg, A. B.;
Matson, D. J.; McDermott, J. S.; Patel, V. F.; Wilenkin, B.; Zou, A.; McDonough, S. I.; DiMauro E. F. Bioorg. Med. Chem. Lett. 2012, 22, 1055.
(h) Chakka, N.; Bregman, H.; Du, B.; Nguyen, H. N.; Buchanan, J. L.; Feric, E.; Ligutti, J.; Liu, D.; McDermott, J. S.; Zou, A.; McDonough, S.
I.; DiMauro E. F. Bioorg. Med. Chem. Lett. 2012, 22, 2052. (i) Kers, I.; Csjernyik, G.; Macsari, I.; Nylöf, M.; Sandberg, L.; Skogholm, K.;
Bueters, T.; Eriksson, A. B.; Oerther, S.; Lund, P.-E.; Venyike, E.; Nyström, J.-E.; Besidski, Y. Bioorg. Med. Chem. Lett. 2012, 22, 5618. (j) Kers,
I.; Macsari, I.; Csjernyik, G.; Nylöf, M.; Skogholm, K.; Sandberg, L.; Minidis, A.; Bueters, T.; Malmborg, J.; Eriksson, A. B.; Lund, P.-E.;
Venyike, E.; Luo, L.; Nyström, J.-K.; Besidski, Y. Bioorg. Med. Chem. Lett. 2012, 22, 6108.
5.
The in vitro evaluation of the compounds was performed utilizing the IonWorks Quattro automated electrophysiology platform. This platform
enabled us to evaluate the inhibitory activity of each NaV in various states. In each NaV assay, the inhibitory activity was evaluated in an
inactivated state.
6.
7.
8.
Catterall, W. A.; Goldin, A. L.; Waxman, S. G. Pharmacol. Rev. 2005, 57, 397.
Finkel, A.; Wittel, A.; Yang, N.; Handran, S.; Hughes, J.; Costantin, J. J. Biomol. Screen. 2006, 11, 488.
(a) For the preparation of piperazine intermediates for 1 and 2b, see: Smid, P.; Coolen, H. K. A. C.; Keizer, H. G.; van Hes, R.; de Moes, J.-P.;
den Hartog, A. P.; Stork, B.; Plekkenpol, R. H.; Niemann, L. C.; Stroomer, C. N. J.; Tulp, M. T. M.; van Stuivenberg, H. H.; McCreary, A. C.;
Hesselink, M. B.; Herremans, A. H. J.; Kruse, C. G. J. Med. Chem. 2005, 48, 6855. (b) For the preparation of piperazine intermediate for 2d, see:
Gant, T. G.; Sarshar. S. Patent US2010/119622, 2010. (c) For the preparation of piperidine intermediate for 2e, see: Tsushima, M.; Tadauchi, K.;
Asai, K.; Miike, N.; Imai, M.; Kudo, T. Patent: US2003/171370, 2003. (d) For the preparation of piperidine intermediate for 2f, see: Nerenberg, J.
B.; Erb, J. M.; Thompson, W. J.; Lee, H.-Y.; Guare, J. P.; Munson, P. M.; Bergman, J. M.; Huff, J. R.; Broten, T. P.; Chang, R. S. L.; Chen, T.
B.; O'Malley, S.; Schorn, T. W.; Scott, A. L. Bioorg. Med. Chem. Lett. 1998, 8, 2467. (e) For the preparation of piperidine intermediate for 2g,
see: Flyren, K.; Bergquist, L. O.; Castro, V. M.; Fotsch, C.; Johansson, L.; Jean, D. J. S.; Sutin, L.; Williams, M. Bioorg. Med. Chem. Lett. 2007,
17, 3421. (f) For the preparation of piperidine intermediate for 2h, see: Fujimoto, T.; Imaeda, Y.; Konishi, N.; Hiroe, K.; Kawamura, M.; Textor,
G. P.; Aertgeerts, K.; Kubo, K. J. Med. Chem. 2010, 53, 3517. (g) For the preparation of piperidine intermediate for 2i, see: Manetti, D.; Martini,
E.; Ghelardini, C.; Dei, S.; Galeotti, N.; Guandalini, L.; Romanelli, M. N.; Scapecchi, S.; Teodori, E.; Bartolini, A.; Gualtieri, F. Bioorg. Med.
Chem. Lett. 2003, 13, 2303. (h) For the preparation of piperidine intermediate for 2j, see: Cheng, C.; Xu, J.; Zhu, R.; Xing, L.; Wang, X.; Hu, Y.
Tetrahedron 2009, 65, 8538.
9.
Suzuki, A. Angew. Chem. Int. Ed. Engl. 2011, 50, 6722.
10. The 1HNMR and mass spectrum of 1-(2-hydroxy-3-{[2-methoxy-4-(trifluoromethyl)benzyl]oxy}propyl)-N-phenylpiperidine-4-carboxamide (9o).
1HNMR (400MHz, CDCl3) δ 1.81-1.98 (4H, m), 2.07 (1H, t, J = 10.8 Hz), 2.24-2.53 (4H, m), 2.95 (1H, d, J = 11.7 Hz), 3.09 (1H, d, J = 11.3 Hz),