Silicon switch approach in TRPV1 antagonist MK-056 and its analogues.
In searching for opportunities to exploit the benefits of silicon in TRPV1 research, we tried to investigate the pharmacological effects of sila-substitution (C/Si exchange) of tert-butyl group in the MK-056 series. Compound 13a, with a 4-positioned trimethylsilanyl group on the B ring in place of tert-butyl group, exhibited the most potent antagonist activity with IC(50) values of 0.15 microM, which is almost equipotent with that of MK-056. This is the first example that tert-butyl group on MK-056 series can be replaced to the other substituent without loss of activity.
Chang
Minsun
M
Department of Biological Science, Sookmyung Women's University, Yongsan-gu, Seoul 140-742, Republic of Korea.
Park
Seol-Rin
SR
Kim
Juhyun
J
Jang
Mijung
M
Park
Jeong Hyun
JH
Park
Ji Eun
JE
Park
Hyeung-Geun
HG
Suh
Young-Ger
YG
Jeong
Yeon Su
YS
Park
Young-Ho
YH
Kim
Hee-Doo
HD
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D015394:Molecular Structure; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010670:Phenylthiourea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012825:Silicon / Q000737:chemistry*; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D010670:Phenylthiourea; C037877:benzylthiourea; D002118:Calcium; D012825:Silicon