title: Anti-inflammatory effect and selectivity profile of AS1940477, a novel and potent p38 mitogen-activated protein kinase inhibitor.
abstract: Given the key role p38 mitogen-activated protein kinase (MAPK) plays in inflammatory responses through the production of cytokines and inflammatory mediators, its inhibition is considered a promising therapeutic strategy for chronic inflammatory diseases such as rheumatoid arthritis, psoriasis, inflammatory bowel disease, and chronic obstructive pulmonary disease. Here, we evaluated the anti-inflammatory effect and selectivity profile of the novel p38 MAPK inhibitor AS1940477. AS1940477 inhibited the enzymatic activity of recombinant p38α and β isoforms but showed no effect against other 100 protein kinases including p38γ and δ isoforms. We also confirmed the selectivity of AS1940477 in the intracellular signaling pathway. In human peripheral blood mononuclear cells, AS1940477 inhibited lipopolysaccharide (LPS)- or phytohemagglutinin A (PHA)-induced production of proinflammatory cytokines, including TNFα, IL-1β, and IL-6 at low concentrations (LPS/TNFα, IC(50)=0.45n M; PHA/TNFα, IC(50)=0.40 nM). In addition, equivalent concentrations of AS1940477 that inhibited cytokine production also inhibited TNFα- and IL-1 β-induced production of IL-6, PGE(2), and MMP-3 in human synovial stromal cells. AS1940477 was also found to potently inhibit TNF production in whole blood (IC(50)=12 nM) and effectively inhibited TNFα production induced by systemically administered LPS in rats at less than 0.1mg/kg (ED(50)=0.053 mg/kg) with an anti-inflammatory effect lasting for 20h after oral administration. Overall, this study demonstrated that AS1940477 is a novel and potent p38 MAPK inhibitor and may be useful as a promising anti-inflammatory agent for treating inflammatory disorders.
authors.affiliation: Pharmacology Research Laboratories, Astellas Pharma Inc, 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan. masaomi.terajima@astellas.com
authors.forename: Masaomi
authors.initials: M
authors.lastname: Terajima
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Inoue
authors.forename: Katsue
authors.initials: K
authors.lastname: Magari
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Yamazaki
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Higashi
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Mizuhara
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D004731:Endotoxins / Q000633:toxicity; D005260:Female; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011724:Pyridazines / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D013379:Substrate Specificity; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C581547:6-(2-(4-fluorophenyl)-6-(hydroxymethyl)-4,5,6,7-tetrahydropyrazolo(1,5-a)pyrimidin-3-yl)-2-(2-methylphenyl)pyridazin-3(2H)-one; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004731:Endotoxins; D053583:Interleukin-1beta; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D011743:Pyrimidines; D014409:Tumor Necrosis Factor-alpha; C062482:pyridazine; D048051:p38 Mitogen-Activated Protein Kinases