Synthesis and structural optimization of multiple H-bonding region of diarylalkyl (thio)amides as novel TRPV1 antagonists.
Structural optimization of multiple H-bonding region and structure-activity relationship of diarylalkyl amides/thioamides as novel TRPV1 antagonists are described. In particular, we identified amide 34o and thioamides 35o and 35r, of which antagonistic activities were highly enhanced by an incorporation of cyano or vinyl-substituent to the multiple H-bonding region. They exhibited potent (45)Ca(2+) uptake inhibitions in rat DRG neuron with IC(50)s of 25, 32 and 28 nM, respectively.
Li
Fu-Nan
FN
College of Pharmacy, Seoul National University, Gwanak-gu, Seoul 151-742, Republic of Korea.
Kim
Nam-Jung
NJ
Chang
Dong-Jo
DJ
Jang
Jaebong
J
Jang
Hannah
H
Jung
Jong-Wha
JW
Min
Kyung-Hoon
KH
Jeong
Yeon-Su
YS
Kim
Sun-Young
SY
Park
Young-Ho
YH
Kim
Hee-Doo
HD
Park
Hyeung-Geun
HG
Suh
Young-Ger
YG
D000577:Amides / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D020128:Inhibitory Concentration 50; D009474:Neurons / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*
D000577:Amides; D050916:TRPV Cation Channels; D002118:Calcium