Discovery of a potent, metabolically stabilized resorcylic lactone as an anti-inflammatory lead

被引：25

作者：

Du, H. ^{[1
]}

Matsushima, T. ^{[2
]}

Spyvee, M. ^{[1
]}

Goto, M. ^{[2
]}

Shirota, H. ^{[1
]}

Gusovsky, F. ^{[1
]}

Chiba, K. ^{[2
]}

Kotake, M. ^{[2
]}

Yoneda, N. ^{[2
]}

Eguchi, Y. ^{[2
]}

DiPietro, L. ^{[1
]}

Harmange, J. -C. ^{[1
]}

Gilbert, S. ^{[1
]}

Li, X. -Y. ^{[1
]}

Davis, H. ^{[1
]}

Jiang, Y. ^{[1
]}

Zhang, Z. ^{[1
]}

Pelletier, R. ^{[1
]}

Wong, N. ^{[1
]}

Sakurai, H. ^{[2
]}

Yang, H. ^{[1
]}

Ito-Igarashi, H. ^{[2
]}

Kimura, A. ^{[2
]}

Kuboi, Y. ^{[2
]}

Mizui, Y. ^{[2
]}

Tanaka, I. ^{[2
]}

Ikemori-Kawada, M. ^{[2
]}

Kawakami, Y. ^{[2
]}

Inoue, A. ^{[2
]}

Kawai, T. ^{[2
]}

Kishi, Y. ^{[3
]}

Wang, Y. ^{[1
]}

机构：

[1] Eisai Res Inst Boston, Andover, MA 01810 USA

[2] Eisai Tsukuba Res Labs, Tsukuba, Ibaraki 3002635, Japan

[3] Eisai & Co Ltd, Sci Advisory Board, Bunkyo Ku, Tokyo 1128088, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2009年 / 19卷 / 21期

关键词：

MEKK1; MEK1; Resorcylic acid; Anti-inflammatory; ER-803064; LL-Z1640-2; MACROLIDES; HYPOTHEMYCIN; KINASE; INHIBITION; ACTIVATION; RADICICOL;

D O I：

10.1016/j.bmcl.2009.08.096

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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. (c) 2009 Elsevier Ltd. All rights reserved.

引用

页码：6196 / 6199

页数：4

共 27 条

[1] GEOMETRICAL REACTION COORDINATES .2. NUCLEOPHILIC ADDITION TO A CARBONYL GROUP [J].