C. D. Haffner et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6983–6988
6987
O
Cl
N
N
H
O
N
NH2
b
a
N
N
N
S
S
S
31
32
33
O
N
N
H
c
F
N
S
34
O
Br
NH
N
N
d
f
e
O
S
S
S
37
35
36
O
N
NH2
N
N
H
g
F
S
S
38
39
Scheme 4. Reagents and conditions: (a) 3, THF, À78 °C, nBuLi; (b) CH2Cl2, TFA; (c) 4-fluorobenzoyl chloride, CH2Cl2, iPr2NEt; (d) toluene, Pd2dba3, aniline, RuPhos, NaOtBu; (e)
NaH, DMF, KI, 3-bromo-N-phthalimide; (f) hydrazine, EtOH; (g) CH2Cl2, iPr2NEt, 4-fluorobenzoyl chloride.
7. (a) Xu, J.; Wang, P.; Li, Y.; Li, G.; Kaczmarek, L. K.; Wu, Y.; Koni, P. A.;
increases its affinity for it. It is unclear whether this is electronic or
steric in nature. When both the oxygen atoms and nitrogen are re-
Flavell, R. A.; Desire, G. V. Proc. Natl. Acad. Sci. 2004, 101, 3112; (b) Li, Y.;
Wang, P.; Xu, J.; Desire, G. V. Am. J. Physiol. Cell Physiol. 2006, 290, C345; (c)
Xu, J.; Koni, P. A.; Wang, P.; Li, G.; Kaczmarek, L.; Wu, Y.; Li, Y.; Flavell, R.
A.; Desir, G. V. Hum. Mol. Genet. 2003, 12, 551; (d) Desir, G. V. Expert Opin.
Ther. Targets 2005, 9, 571; (e) Tucker, K.; Overton, J. M.; Fadool, D. A. Int. J.
Obesity 2008, 1.
moved to give benzothiophene 39, the compound loses all of its
activity (IC50 >50 M).
In conclusion, we describe herein
l
a
series of novel
1,1-dioxo-1,2-benzothiazole derivatives several of which showed
similar potency to the known Kv1.3 inhibitor PAP-1 when tested
under the IonWorks patch clamp assay conditions. We found,
through extensive structural modifications, that this template
showed the most flexibility in regards to the potency around the
terminal carboxamide moiety and propyl side chain. Other regions
of the molecule were less amenable to structural changes. The de-
tails of additional work within this chemotype will be forthcoming.
8. Tschritter, O.; Machicao, F.; Stefan, N.; Schafer, S.; Weigert, C.; Staiger, H.;
Spieth, C.; Haring, H.-U.; Fritsche, A. J. Clin. Endocrinol. Metab. 2006, 91,
654.
9. (a) Panyi, G.; Possani, L. D.; Rodriguez de la Vega, R. C.; Gaspar, R.; Varga, Z.
Curr. Pharm. Des. 2006, 12, 2199; (b) Schmalhofer, W. A.; Bao, J.; McManus, O.
B.; Green, B.; Matyskiela, M.; Wunderler, D.; Bugianesi, R. M.; Felix, J. P.;
Hanner, M.; Linde-Arias, A.-R.; Ponte, C. G.; Velasco, L.; Koo, G.; Staruch, M. J.;
Miao, S.; Parsons, W. H.; Rupprecht, K.; Slaughter, R. S.; Kaczorowski, G. J.;
Garcia, M. L. Biochemistry 2002, 41, 7781; (c) Pennington, M. W.; Beeton, C.;
Galea, C. A.; Smith, B. J.; Chi, V.; Monaghan, K. P.; Garcia, A.; Rangaraju, S.;
Giuffrida, A.; Plank, D.; Crossley, G.; Nugent, D.; Khaytin, I.; LeFievere, Y.;
Peshenko, I.; Dixon, C.; Chauhan, S.; Orzel, A.; Inoue, T.; Hu, X.; Moore, R. V.;
Norton, R. S.; Chandy, K. G. Mol. Pharmacol. 2009, 75, 762; (d) Pegoraro, S.; Lang,
M.; Dreker, T.; Kraus, J.; Hamm, S.; Meere, C.; Feurle, J.; Tasler, S.; Prutting, S.;
Kuras, Z.; Visan, V.; Grissmer, S. Bioorg. Med. Chem. Lett. 2009, 19, 2299;
(e) Schmitz, A.; Sankaranarayanan, A.; Azam, P.; Schmidt-Lassen, K.; Homerick,
D.; Hansel, W.; Wulff, H. Mol. Pharmacol. 2005, 68, 1254; (f) Bodendiek, S. B.;
Mahieux, C.; Hansel, W.; Wulff, H. Eur. J. Med. Chem. 2009, 44, 1838; (g) Garcia-
Calvo, M.; Leonard, R. J.; Novick, J.; Stevens, S. P.; Schmalhofer, W.;
Kaczorowski, G. J.; Garcia, M. L. J. Biol. Chem. 1993, 268, 18866; (h) Oguchi,
T.; Watanabe, K.; Ohkubo, K.; Abe, H.; Katoh, T. Chem. Eur. J. 2009, 15, 2826;
(i) Miao, S.; Bao, J.; Garcia, M. L.; Goulet, J. L.; Hong, X. J.; Kaczorowski, G. J.;
Kayser, F.; Koo, G. C.; Kotliar, A.; Schmalhofer, W. A.; Shah, K.; Sinclair, P. J.;
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11. Frozen CGE22 cells were thawed and then were transiently transduced to
express human Kv1.3 using 5% (MOI 50-75) Bacmam baculovirus .The cells
were grown adherently for 24 h, cultured, plated at 5000 cells per well and
assayed in an IonWorks PPC format. Channel blockers were detected by
depolarizing membrane potentials resulting in a shift in voltage dependence to
more positive potential. This was accomplished by performing a series of
voltage pulses from À70 mV (resting potential) to +40 mV; the maximum
channel activation and conduction potential. Psora-4, a known potent small
molecule inhibitor of Kv1.3 (IC50 = 724 nM under these assay conditions) was
used as the standard for this assay. The assay was configured to pick up both
tonic block and use-dependent inhibition of the compounds tested against
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