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 v...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2010-05, Vol.20 (10), p.3047-3049
Hauptverfasser:	Shen, Yongchun, Du, Hong, Kotake, Makoto, Matsushima, Tomohiro, Goto, Masaki, Shirota, Hiroshi, Gusovsky, Fabian, Li, Xiangyi, Jiang, Yimin, Schiller, Shawn, Spyvee, Mark, Davis, Heather, Zhang, Zhiyi, Pelletier, Robert, Ikemori-Kawada, Megumi, Kawakami, Yoshiyuki, Inoue, Atsushi, Wang, Yuan
Format:	Artikel
Sprache:	eng
Schlagworte:	Anti-inflammatory Anti-Inflammatory Agents - chemical synthesis Anti-Inflammatory Agents - chemistry Anti-Inflammatory Agents - pharmacology Biological and medical sciences Bones, joints and connective tissue. Antiinflammatory agents Drug Discovery f152A1 Lactones - chemical synthesis Lactones - chemistry Lactones - pharmacology LL-Z1640-2 MAP Kinase Kinase 1 - antagonists & inhibitors MAP Kinase Kinase 1 - metabolism Medical sciences Pharmacology. Drug treatments Resorcylic lactone Structure-Activity Relationship
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Zusammenfassung:	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.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2010.03.119