H. N. Seo et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5740–5743
5743
3. (a) Flatters, S. J. L. Drugs Future 2005, 30, 573; (b)
Nelson, M. T.; Todorovic, S. M. Curr. Pharm. Des. 2006,
12, 2189; (c) Perez-Reyes, E. Physiol. Rev. 2003, 83, 117;
(d) Vassort, G.; Alvarez, J. J. Cardiovasc. Electrophysiol.
1994, 5, 376.
4. (a) Clozel, J.; Ertel, E.; Ertel, S. J. Hypertens. Suppl. 1997,
15, S17; (b) Hermsmeyer, K.; Mishra, S.; Miyagawa, K.;
Minshall, R. Clin. Ther. 1997, 19, 18; (c) Van der Vring, J.;
Cleophas, T.; Van der Wall, E.; Niemeyer, M. Am. J.
Ther. 1999, 6, 229.
10. (a) Kim, T.; Choi, J.; Kim, S.; Kwon, O.; Nah, S. Y.; Han,
Y. S.; Rhim, H. Biochem. Biophys. Res. Commun. 2004,
324, 401; (b) For the recordings of a1G T-type Ca2+
currents, the standard whole-cell patch–clamp method was
utilized. Briefly, borosilicate glass electrodes with a resis-
tance of 3–4 MX were pulled and filled with the internal
solution containing (in mM): 130 KCl, 11 EGTA, 5 Mg-
ATP, and 10 Hepes (pH 7.4). The external solution
contained (in mM): 140 NaCl, 2 CaCl2, 10 Hepes, and 10
glucose (pH 7.4). a1G T-type Ca2+ currents were evoked
every 15 s by a 50 ms depolarizing voltage step from
ꢀ100 mV to ꢀ30 mV. The molar concentrations of test
compounds required to produce 50% inhibition of peak
currents (IC50) were determined from fitting raw data into
dose–response curves. The current recordings were
obtained using an EPC-9 amplifier and Pulse/Pulsefit
software program (HEKA, Germany).
5. Asirvatham, S.; Sebastian, C.; Thadani, U. Drug Saf.
1998, 19, 23.
6. (a) Park, J. H.; Choi, J. K.; Lee, E.; Lee, J. K.; Rhim, H.;
Seo, S. H.; Kim, Y.; Doddareddy, M. R.; Pae, A. N.;
Kang, J.; Roh, E. J. Bioorg. Med. Chem. 2007, 15, 1409;
(b) Doddareddy, M. R.; Choo, H.; Cho, Y. S.; Rhim, H.;
Koh, H. Y.; Lee, J.-H.; Jeong, S.-W.; Pae, A. N. Bioorg.
Med. Chem. 2007, 15, 1091; (c) Jo, M. N.; Seo, H. J.; Kim,
Y.; Seo, S. H.; Rhim, H.; Cho, Y. S.; Cha, J. H.; Koh, H.
Y.; Choo, H.; Pae, A. N. Bioorg. Med. Chem. 2007, 15,
365; (d) Ku, I. W.; Cho, S.; Doddareddy, M. R.; Jang, M.
S.; Keum, G.; Lee, J.-H.; Chung, B. Y.; Kim, Y.; Rhim,
H.; Kang, S. B. Bioorg. Med. Chem. Lett. 2006, 16, 5244;
(e) Furukawa, T.; Yamada, O.; Matsumoto, H.; Yamash-
ita, T. WO 2005051402, 2005; (f) McCalmont, W. F.;
Heady, T. N.; Patterson, J. R.; Lindenmuth, M. A.;
Haverstick, D. M.; Gray, L. S.; MacDonald, T. L. Bioorg.
Med. Chem. Lett. 2004, 14, 3691; (g) Jung, H. K.;
Doddareddy, M. R.; Cha, J. H.; Rhim, H.; Cho, Y. S.;
Koh, H. Y.; Jung, B. Y.; Pae, A. N. Bioorg. Med. Chem.
2004, 12, 3965; (h) Kumar, P. P.; Stotz, S. C.; Parama-
shivappa, R.; Beedle, A. M.; Zamponi, G. W.; Rao, A. S.
Mol. Pharmacol. 2002, 61, 649.
7. (a) Choi, J. Y.; Seo, H. N.; Lee, M. J.; Park, S. J.; Park, S.
J.; Jeon, J. Y.; Kang, J. H.; Pae, A. N.; Rhim, H.; Lee, J.
Y. Bioorg. Med. Chem. Lett. 2007, 17, 471; (b) Park, S. J.;
Park, S. J.; Lee, M. J.; Rhim, H.; Kim, Y.; Lee, J.-H.;
Chung, B. Y.; Lee, J. Y. Bioorg. Med. Chem. 2006, 14,
3502; (c) Rhim, H.; Lee, Y. S.; Park, S. J.; Chung, B. Y.;
Lee, J. Y. Bioorg. Med. Chem. Lett. 2005, 15, 283; (d) Lee,
Y. S.; Lee, B. H.; Park, S. J.; Kang, S. B.; Rhim, H.; Park,
J.-Y.; Lee, J.-H.; Jeong, S.-W.; Lee, J. Y. Bioorg. Med.
Chem. Lett. 2004, 14, 3379.
11. Kim, Y.; Seo, S.; Kim, D.; Rhim, H. The 11th Annual
Conference and Exhibition, Geneva, Switzerland, Septem-
ber 11–15, 2005; Society for Biomolecular Screening:
Danbury, CT, 2005; P07016.
12. Chuang, R. S.; Jaffe, H.; Cribbs, L.; Perez-Reyes, E.;
Swartz, K. J. Nat. Neurosci. 1998, 1, 668.
13. Spectral data of the compounds 10 and 11: for
compound 10 (KYS05090), 1H NMR (400 MHz,
CDCl3)d 7.72–6.98 (18H, m, Ph), 5.32 (1H, dd, J = 9.1
and 4.6 Hz, COCH2CH), 4.50 (2 H, d, J = 5.8 Hz,
PhCH2–), 3.50–3.20 (2 H, m, CH3N–CH2), 2.71–2.33
(4 H, CH3–N and COCH), 2.44 (1H, dd, J = 14.5 and
5.2 Hz, COCH), 2.30–2.29 (2 H, m, –NCH2), 2.21 (6 H,
s, 2 · N–CH3), 1.65–1.35 (4 H, m, 2 · –CH2), 1.25–1.10
(2 H, m, CH2); 13C NMR (100 MHz, CDCl3)d 170.1,
153.9, 145.3, 143.8, 140.4, 138.4, 136.7, 128.8, 128.6,
128.1, 128.0, 127.8, 127.4, 127.1, 127.0, 126.2, 125.1,
122.8, 122.4, 122.2, 61.2, 59.7, 49.5, 45.2, 43.8, 41.8,
35.3, 27.1, 27.0, 24.7; MS (FAB+), m/z (relative inten-
sity, %) 596.7([M+Na]+, 100), 574.7 ([M+H]+, 30); MS
(FAB-), m/z (relative intensity, %) 572.7([M-H]+, 100);
HRMS (FAB+) calcd for C37H44N5O: [M+H]+ =
574.3546,
found = 574.3516;
for
compound
11
(KYS05089), 1H NMR (400 MHz, CDCl3)d 7.52–6.88
(13 H, m, Ph), 5.11 (1H, dd, J = 10.4 and 4.5 Hz,
COCH2CH), 3.75 (3H, s, OCH3), 3.50 (1H, m, CH3N–
CH), 3.15 (1H, m, CH3N–CH), 2.88–2.82 (4H, m, CH3–
N and COCH), 2.51 (1H, dd, J = 15.5 and 4.6 Hz,
COCH), 2.25–2.23 (2H, m, –NCH2), 2.20 (6H, s, 2 · N–
CH3), 1.52–1.45 (4H, m, 2 · –CH2), 1.24–1.23 (2H, m,
CH2); 13C NMR (100 MHz, CDCl3)d 171.9, 153.4, 145.4,
144.2, 140.3, 136.8, 128.8, 128.4, 127.9, 127.1, 126.8,
125.4, 124.8, 122.9, 122.6, 122.1, 61.2, 59.7, 49.5, 45.2,
43.8, 41.8, 35.3, 27.1, 27.0, 24.7; HRMS (FAB+) calcd
for C31H39N4O2: [M+H]+ = 499.3073, found = 499.3060.
8. Phuan, P.-W.; Kozlowski, M. C. J. Org. Chem. 2002, 67,
6339.
9. (a) Fattori, D.; Rossi, C.; Fincham, C. I.; Caciagli, V.;
Catrambone, F.; D’Andrea, P.; Felicetti, P.; Gensini, M.;
Marastoni, E.; Nannicini, R.; Paris, M.; Terracciano, R.;
Bressan, A.; Giuliani, S.; Maggi, C. A.; Meini, S.; Valenti,
C.; Quartara, L. J. Med. Chem. 2007, 50, 550; (b)
Ramamohan, R. D.; Sankara, R. C.; Pamujula, S. WO
02090339, 2002.