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

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 21, 2009, Pages 6196-6199

  Du, H ^a   Matsushima, T ^b   Spyvee, M ^a   Goto, M ^b   Shirota, H ^a   Gusovsky, F ^a   Chiba, K ^b   Kotake, M ^b   Yoneda, N ^b   Eguchi, Y ^b   DiPietro, L ^a   Harmange, J C ^a   Gilbert, S ^a   Li, X Y ^a   Davis, H ^a   Jiang, Y ^a   Zhang, Z ^a   Pelletier, R ^a   Wong, N ^a   Sakurai, H ^b   Yang, H ^a   Ito Igarashi, H ^b   Kimura, A ^b   Kuboi, Y ^b   Mizui, Y ^b   Tanaka, I ^b   Ikemori Kawada, M ^b   Kawakami, Y ^b   Inoue, A ^b   Kawai, T ^b   Kishi, Y ^b   Wang, Y ^a   more..

^a EISAI RESEARCH INSTITUTE   (United States)

^b EISAI CO LTD   (Japan)

Author keywords

Anti inflammatory; ER 803064; MEK1; MEKK1; Resorcylic acid

Indexed keywords

ANTIINFLAMMATORY AGENT; ER 803064; F 152 A 1; F152 A1; LACTONE DERIVATIVE; LL Z1640 2; LLZ 16402; NATURAL PRODUCT; RESORCYLIC LACTONE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANTIINFLAMMATORY ACTIVITY; AREA UNDER THE CURVE; ARTICLE; CONTROLLED STUDY; DRUG ACTIVITY; DRUG BLOOD LEVEL; DRUG ELIMINATION; DRUG INHIBITION; DRUG METABOLISM; DRUG POTENCY; DRUG SCREENING; DRUG SYNTHESIS; IN VITRO STUDY; IN VIVO STUDY; ISOMERIZATION; METABOLIC INHIBITION; NONHUMAN; PHENOTYPE; STRUCTURE ACTIVITY RELATION;

ANIMALS; ANTI-INFLAMMATORY AGENTS; DRUG DESIGN; HUMANS; INTERLEUKIN-6; LACTONES; MICE; MICROSOMES, LIVER;

ANIMALIA;

EID: 71749111541     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.08.096     Document Type: Article

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29. 4 cells/well onto 96-well plate, then were cultured in the presence or absence of test compounds for 30 min, followed by stimulation with 100 ng/ml of lipopolysaccharide (LPS; E.coli 0127:B08 or 011:B4). Total volume of the reaction mixture was 200 μL. After the cultivation for 24-48 hrs, culture supernatant was harvested and alkaline phosphatase activity in the supernatant was measured.
30. 2PO4 water solution buffered with phosphoric acid to pH=3.5. The pump speed is 1.1 mL/min. The amount of unchanged form was estimated from the peak area, and the remaining % at each time point of the incubation was calculated by comparing with the area at 0 min.
31. The test compounds were co-injected with LPS through tail vain in the formulation with 10 % cyclodextrin. At 3 hours after the injection, the peripheral blood was harvested and plasma was separated for the determination of IL-6 by ELISA. Each column represents mean with SEM (n = 6 - 8). *P<0.05; statistically significant as compared with the LPS-treated control group in Dunnett's multiple comparison post hoc analysis.