August 2011
1037
21) Kim H. S., Kim Y., Doddareddy M. R., Seo S. H., Rhim H., Tae J., Pae
A. N., Choo H., Cho Y. S., Bioorg. Med. Chem. Lett., 17, 476—481
(2007).
22) 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., 15, 1091—1105
(2007).
23) 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.,
15, 1409—1419 (2007).
24) Seo H. N., Choi J. Y., Choe Y. J., Kim Y., Rhim H., Lee S. H., Kim J.,
Joo D. J., Lee J. Y., Bioorg. Med. Chem. Lett., 17, 5740—5743 (2007).
25) Hangeland J. J., Cheney D. L., Friends T. J., Swartz S., Levesque P. C.,
Rich A. J., Sun L., Bridal T. R., Adam L. P., Normandin D. E., Mu-
rugesan N., Ewing W. R., Bioorg. Med. Chem. Lett., 18, 474—478
(2008).
26) Oh Y., Kim Y., Seo S. H., Lee J. K., Rhim H., Pae A. N., Jeong K.-S.,
Choo H., Cho Y. S., Bull. Korean Chem. Soc., 29, 1881—1882 (2008).
27) Shipe W. D., Barrow J. C., Yang Z.-Q., Lindsley C. W., Yang F. V.,
Schlegel K.-A. S., Shu Y., Rittle K. E., Bock M. G., Hartman G. D.,
Tang C., Ballard J. E., Kuo Y., Adarayan E. D., Prueksaritanont T.,
Zrada M. M., Uebele V. N., Nuss C. E., Connolly T. M., Doran S. M.,
Fox S. V., Kraus R. L., Marino M. J., Graufelds V. K., Vargas H. M.,
Bunting P. B., Hasbun-Manning M., Evans R. M., Koblan K. S.,
Renger J. J., J. Med. Chem., 51, 3692—3695 (2008).
28) Heo J. H., Seo H. N., Choe Y. J., Kim S., Oh C. R., Kim Y. D., Rhim
H., Choo D. J., Kim J., Lee J. Y., Bioorg. Med. Chem. Lett., 18, 3899—
3901 (2008).
29) Lee H. K., Lee Y. S., Roh E. J., Rhim H., Lee J. Y., Shin K. J., Bioorg.
Med. Chem. Lett., 18, 4424—4427 (2008).
sure (MBP) was calculated from the following formula; MBPꢁDBPꢀ
(SBPꢃDBP)/3, where DBP represents diastolic blood pressure and SBP rep-
resents systolic blood pressure. Heart rate was measured with a cardiota-
chometer (Nihon Kohden AT-600G) triggered by the pulsewave of blood
pressure. A ED30 value that mean the dose of the compounds producing a
30% reduction from initial MBP, was determined by linear regression.
Pharmacology in Vivo Study ( p.o.) Male SHR rats (300—350 g) were
anesthetized with pentobarbital (60 mg/kg i.p.), and a polyethylene cannula
(PE-50) was implanted in the common carotid artery. The other end of the
catheter was then routed to an exit site at the back of the neck. Animals were
allowed a 1- to 2-d recovery period after the operation, during which time
they were housed individually with free access to rat chow and water. Blood
pressure was measured using a pressure transducer (Nihon Kohden DX-100)
coupled to the carotid artery cannula and a pressure amplifier (Nihon Ko-
hden AP-621G) and was continuously recorded using a polygraph system.
Heart rate was measured with a cardiotachometer (Nihon Kohden AT-600G)
triggered by the blood pressure pulsewave. After a 30-min measurement pe-
riod to establish baseline values, test compounds were orally administrated
as an aqueous solution by gavage at doses of 3 and 10 mg/kg (the salt form).
Acknowledgements We thank Dr. Fukushi Hirayama for his helpful
support in preparing this manuscript. We are also grateful to Dr. Hironori
Harada, Dr. Masakazu Imamura, and Mr. Kyoichi Maeno for their useful ad-
vice. Finally, we wish to thank Mr. Kazuhiko Mizukami, Miss Yuriko
Komiya, Dr. Noriyasu Kanie, Mr. Satoshi Konagai, and Mr. Eisaku Ya-
mamoto for performing the biological experiments, and the members of the
Division of Analytical Science Laboratories for elemental analysis and spec-
tral measurements.
30) Yang Z.-Q., Barrow J. C., Shipe W. D., Schlegel K.-A. S., Shu Y., Yang
F. V., Lindsley C. W., Rittle K. E., Bock M. G., Hartman G. D., Uebele
V. N., Nuss C. E., Fox S. V., Kraus R. L., Doran S. M., Connolly T. M.,
Tang C., Ballard J. E., Kuo Y., Adarayan E. D., Prueksaritanont T.,
Zrada M. M., Marino M. J., Graufelds V. K., DiLella A. G., Reynolds
I. J., Vargas H. M., Bunting P. B., Woltmann R. F., Magee M. M.,
Koblan K. S., Renger J. J., J. Med. Chem., 51, 6471—6477 (2008).
31) Jeong J. A., Cho H., Jung S. Y., Kang H. B., Park J. Y., Kim J., Choo
D. J., Lee J. Y., Bioorg. Med. Chem. Lett., 20, 38—41 (2010).
32) Gu S. J., Lee J. K., Pae A. N., Chung H. J., Rhim H., Han S. Y., Min
S.-J., Cho Y. S., Bioorg. Med. Chem. Lett., 20, 2705—2708 (2010).
33) Lee J. E., Koh H. Y., Seo S. H., Baek Y. Y., Rhim H., Cho Y. S., Choo
H., Pae A. N., Bioorg. Med. Chem. Lett., 20, 4219—4222 (2010).
34) Smith E. M., Sorota S., Kim H. M., McKittrick B. A., Nechuta T. L.,
Bennett C., Knutson C., Burnett D. A., Kieselgof J., Tan Z., Rindgen
D., Bridal T., Zhou X., Jia Y.-P., Dong Z., Mullins D., Zhang X.,
Priestley T., Correll C. C., Tulshian D., Czarniecki M., Greenlee W. J.,
Bioorg. Med. Chem. Lett., 20, 4602—4606 (2010).
References and Notes
1) Calhoun D. A., Jones D., Textor S., Goff D. C., Murphy T. P., Toto R.
D., White A., Cushman W. C., White W., Sica D., Ferdinand K., Giles
T. D., Falkner B., Carey R. M., Hypertension, 51, 1403—1419 (2008).
2) Abernethy D. R., Schwartz J. B., N. Engl. J. Med., 341, 1447—1457
(1999).
3) Ernst M. E., Kelly M. W., Pharmacotherapy, 18, 463—485 (1998).
4) Mangoni M. E., Couette B., Marger L., Bourinet E., Striessnig J., Nar-
geot J., Prog. Biophys. Mol. Biol., 90, 38—63 (2006).
5) Learanguer V., Monteil A., Bourinet E., Dayanithi G., Nargeot J., Am.
J. Physiol. Heart Circ. Physiol., 279, H2540—H2548 (2000).
6) Wagner C., Krämer B. K., Hinder M., Kieninger M., Kurtz A., Br. J.
Pharmacol., 124, 579—585 (1998).
7) Mullins M. E., Horowitz B. Z., Linden D. H. J., Smith G. W., Norton
R. L., Stump J., JAMA, 280, 157—158 (1998).
8) SoRelle R., Circulation, 98, 831—832 (1998).
9) Kumar P. P., Stotz S. C., Paramashivappa R., Beedle A. M., Zamponi
G. W., Rao A. S., Mol. Pharmacol., 61, 649—658 (2002).
10) Schenck H. A., Lenkowski P. W., Choudhury-Mukherjee I., Ko S.-H.,
Stables J. P., Patel M. K., Brown M. L., Bioorg. Med. Chem., 12,
979—993 (2004).
35) Schlegel K.-A. S., Yang Z.-Q., Reger T. S., Shu Y., Cube R., Rittle K.
E., Bondiskey P., Bock M. G., Hartman G. D., Tang C., Ballard J., Kuo
Y., Prueksaritanont T., Nuss C. E., Doran S. M., Fox S. V., Garson S.
L., Kraus R. L., Li Y., Uebele V. N., Renger J. J., Barrow J. C., Bioorg.
Med. Chem. Lett., 20, 5147—5152 (2010).
11) Doddareddy M. R., Jung H. K., Lee J. Y., Lee Y. S., Cho Y. S., Koh H.
Y., Pae A. N., Bioorg. Med. Chem., 12, 1605—1611 (2004).
12) Doddareddy M. R., Jung H. K., Cha J. H., Cho Y. S., Koh H. Y., Chang
M. H., Pae A. N., Bioorg. Med. Chem., 12, 1613—1621 (2004).
13) 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., 14, 3379—
3384 (2004).
14) 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., 14, 3691—3695 (2004).
15) 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., 12, 3965—3970
(2004).
16) Rhim H., Lee Y. S., Park S. J., Chung B. Y., Lee J. Y., Bioorg. Med.
Chem. Lett., 15, 283—286 (2005).
36) Kam Y. L., Rhee H.-K., Rhim H., Back S. K., Na H. S., Choo H.-Y. P.,
Bioorg. Med. Chem., 18, 5938—5944 (2010).
37) Fritch P. C., Krajewski J., Bioorg. Med. Chem. Lett., 20, 6375—6378
(2010).
38) Choi Y.-H., Baek J., Seo S. H., Lee J. K., Pae A. N., Cho Y. S., Min
S.-J., Bioorg. Med. Chem. Lett., 21, 215—219 (2011).
39) Reger T. S., Yang Z.-Q., Schlegel K.-A. S., Shu Y., Mattern C., Cube
R., Rittle K. E., McGaughey G. B., Hartman G. D., Tang C., Ballard J.,
Kuo Y., Prueksaritanont T., Nuss C. E., Doran S. M., Fox S. V., Garson
S. L., Li Y., Kraus R. L., Uebele V. N., Renger J. J., Barrow J. C.,
Bioorg. Med. Chem. Lett., 21, 1692—1696 (2011).
40) Unpublished results.
41) Gray N. M., Cheng B. K., Mick S. J., Lair C. M., Contreras P. C., J.
Med. Chem., 32, 1242—1248 (1989).
42) 2-(3-Benzyloxy)ethyl p-toluenesulfonate 20 was synthesized as fol-
lowing scheme.
17) McCalmont W. F., Patterson J. R., Lindenmuth M. A., Heady T. N.,
Haverstick D. M., Gray L. S., Macdonald T. L., Bioorg. Med. Chem.,
13, 3821—3839 (2005).
18) 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., 14, 3502—3511 (2006).
19) 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.,
16, 5244—5248 (2006).
20) 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., 17,
471—475 (2007).
20; 1H-NMR (DMSO-d6) d: 2.41 (3H, s), 2.92 (2H, t, Jꢁ6.8 Hz), 4.21
(2H, t, Jꢁ6.8 Hz), 5.01 (2H, s), 6.66—6.75 (2H, m), 6.81—6.84 (1H,
m), 7.17 (1H, dd, Jꢁ6.4, 7.2 Hz), 7.28 (1H, s), 7.30—7.44 (6H, m),
7.69 (2H, d, Jꢁ8.4 Hz). MS (ESI) m/z: 405 (MꢀꢀNa).