Discovery of a potent, metabolically stabilized resorcylic lactone as an anti-inflammatory lead.
With bioactivity-guided phenotype screenings, a potent anti-inflammatory compound f152A1 has been isolated, characterized and identified as the known natural product LL-Z1640-2. Metabolic instability precluded its use for the study on animal disease models. Via total synthesis, a potent, metabolically stabilized analog ER-803064 has been created; addition of the (S)-Me group at C4 onto f152A1 has resulted in a dramatic improvement on its metabolic stability, while preserving the anti-inflammatory activities.
Du
H
H
Eisai Research Institute of Boston, 4 Corporate Drive, Andover, MA 01810, USA.
Matsushima
T
T
Spyvee
M
M
Goto
M
M
Shirota
H
H
Gusovsky
F
F
Chiba
K
K
Kotake
M
M
Yoneda
N
N
Eguchi
Y
Y
DiPietro
L
L
Harmange
J-C
JC
Gilbert
S
S
Li
X-Y
XY
Davis
H
H
Jiang
Y
Y
Zhang
Z
Z
Pelletier
R
R
Wong
N
N
Sakurai
H
H
Yang
H
H
Ito-Igarashi
H
H
Kimura
A
A
Kuboi
Y
Y
Mizui
Y
Y
Tanaka
I
I
Ikemori-Kawada
M
M
Kawakami
Y
Y
Inoue
A
A
Kawai
T
T
Kishi
Y
Y
Wang
Y
Y
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000493:pharmacokinetics; D015195:Drug Design; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D007783:Lactones / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism
D000893:Anti-Inflammatory Agents; C546157:ER 803064; D015850:Interleukin-6; C118715:LL Z1640-2; D007783:Lactones