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.
Eisai Research Institute of Boston, 4 Corporate Drive, Andover, MA 01810, USA.
H
H
Du
T
T
Matsushima
M
M
Spyvee
M
M
Goto
H
H
Shirota
F
F
Gusovsky
K
K
Chiba
M
M
Kotake
N
N
Yoneda
Y
Y
Eguchi
L
L
DiPietro
J-C
JC
Harmange
S
S
Gilbert
X-Y
XY
Li
H
H
Davis
Y
Y
Jiang
Z
Z
Zhang
R
R
Pelletier
N
N
Wong
H
H
Sakurai
H
H
Yang
H
H
Ito-Igarashi
A
A
Kimura
Y
Y
Kuboi
Y
Y
Mizui
I
I
Tanaka
M
M
Ikemori-Kawada
Y
Y
Kawakami
A
A
Inoue
T
T
Kawai
Y
Y
Kishi
Y
Y
Wang
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