Inhibition of allergic dermal inflammation by the novel imidazopyridazine derivative TAK-427 in a guinea pig experimental model of eczema.
Antigen challenge by patch ovalbumin emulsion induced an eczema-like skin lesion in epicutaneously sensitized guinea pigs. Diseased skin sites were macroscopically characterized by manifestations of dermatitis, such as erythema, edema, and papules, and microscopically characterized by acanthosis, spongiosis, and dermal infiltration by eosinophils. Using such lesions as a model of eczema, we evaluated the potential value of TAK-427 [2-[6-[[3-[4-(diphenylmethoxy)piperidino]propyl]amino] imidazo[1,2-b]pyridazin-2-yl]-2-methylpropionic acid dihydrate] as a therapeutic agent for atopic dermatitis by comparing it with dexamethasone and antihistamines. TAK-427 (0.3-30 mg/kg, p.o.) and dexamethasone (3 and 10 mg/kg, p.o.) inhibited eosinophil infiltration into the skin and ameliorated the dermatitis manifestations and epidermal damage. By contrast, none of the antihistamines tested (azelastine, ketotifen, terfenadine, and cetirizine) suppressed the eosinophil infiltration or dermatitis manifestations. To elucidate the mechanism by which TAK-427 inhibited the development of eczema, we investigated cytokine expression in the affected skin. Both TAK-427 and dexamethasone suppressed the increased mRNA expression of interleukin (IL)-13, granulocyte-macrophage colony-stimulating factor, IL-1alpha, tumor necrosis factor-alpha, interferon-gamma, and IL-8, but not IL-10, suggesting that TAK-427 inhibits allergic inflammation of the skin leading to the development of eczema by inhibiting the expression of proinflammatory cytokines after antigen challenge.
Fukuda
Shigeru
S
Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan. fukuda_shigeru@takeda.co.jp
Midoro
Katsuo
K
Kamei
Takayuki
T
Gyoten
Michiyo
M
Kawano
Yasuhiko
Y
Ashida
Yasuko
Y
Nagaya
Hideaki
H
D000818:Animals; D018926:Anti-Allergic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D016207:Cytokines / Q000096:biosynthesis; D017449:Dermatitis, Allergic Contact / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D003907:Dexamethasone / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004485:Eczema / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D005260:Female; D006168:Guinea Pigs; D006634:Histamine H1 Antagonists / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D011724:Pyridazines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000096:biosynthesis
C469683:2-(6-((3-(4-(diphenylmethoxy)piperidino)propyl)amino)imidazo(1,2-b)pyridazin-2-yl)-2-methylpropionic acid; D018926:Anti-Allergic Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D006634:Histamine H1 Antagonists; D007093:Imidazoles; D011724:Pyridazines; D012333:RNA, Messenger; C062482:pyridazine; C029899:imidazole; D003907:Dexamethasone