Discovery of an in vitro and in vivo potent resorcylic lactone analog of LL-Z1640-2 as anti-inflammatory lead, II.
The potent in vitro lead compound, ER-803064 (2), a MEK1 and MEKK1 inhibitor inspired from natural product LL-Z1640-2 (f152A1), was further optimized to improve in vitro and in vivo potency. The modifications on C14 position led to discovery of the lead compounds 28 and 29, which regained full in vitro potency of f152A1 and showed higher in vivo potency by iv administration.
Shen
Yongchun
Y
Eisai Inc., Andover, MA 01810, USA.
Du
Hong
H
Kotake
Makoto
M
Matsushima
Tomohiro
T
Goto
Masaki
M
Shirota
Hiroshi
H
Gusovsky
Fabian
F
Li
Xiangyi
X
Jiang
Yimin
Y
Schiller
Shawn
S
Spyvee
Mark
M
Davis
Heather
H
Zhang
Zhiyi
Z
Pelletier
Robert
R
Ikemori-Kawada
Megumi
M
Kawakami
Yoshiyuki
Y
Inoue
Atsushi
A
Wang
Yuan
Y
D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D055808:Drug Discovery; D007783:Lactones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship
D000893:Anti-Inflammatory Agents; C118715:LL Z1640-2; D007783:Lactones; D048369:MAP Kinase Kinase 1