E6201, a novel kinase inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-1 and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase-1: in vivo effects on cutaneous inflammatory responses by topical administration.
E6201 [(3S,4R,5Z,8S,9S,11E)-14-(ethylamino)-8,9,16-trihydroxy-3,4-dimethyl-3,4,9,10-tetrahydro-1H-2-benzoxacyclotetradecine-1,7(8H)-dione)] is a novel anti-inflammatory agent that has potent inhibitory effects on the production of proinflammatory cytokines from leukocytes and antiproliferative activity on keratinocytes. To characterize the in vivo pharmacological activity of E6201, topically administered E6201 was evaluated in several different animal models of dermatitis. E6201 formulated as an ointment or cream showed dose-dependent inhibition of croton oil-induced acute edema formation and neutrophil infiltration into mouse skin. In addition, E6201 cream inhibited the 1-fluoro-2,4-dinitrobenzene-induced contact hypersensitivity reaction mediated by T cells in mice. In this model, E6201 cream also suppressed the migration of neutrophils and lymphocytes into the inflammatory site. Pretreatment with E6201 cream attenuated phorbol-12 myristate 13-acetate-induced ornithine decarboxylase activity, a marker of proliferation in epidermis. Furthermore, E6201 ointment showed inhibitory effects on both mezerein-induced and interleukin (IL)-23-induced epidermal hyperplasia. E6201 also suppressed T cell receptor-stimulated IL-17 production from human T cells. These results indicate that topically administered E6201 may be a useful agent for the prevention and treatment of cutaneous inflammatory and hyperproliferative diseases such as psoriasis.
Muramoto
Kenzo
K
Eisai Co., Ltd., Tsukuba Research Laboratories, Ibaraki, Japan. k-muramoto@hhc.eisai.co.jp
Goto
Masaki
M
Inoue
Yoko
Y
Ishii
Naoto
N
Chiba
Ken-ichi
K
Kuboi
Yoshikazu
Y
Omae
Takao
T
Wang
Yuan J
YJ
Gusovsky
Fabian
F
Shirota
Hiroshi
H
D000287:Administration, Topical; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic; D003436:Croton Oil; D004139:Dinitrofluorobenzene; D004224:Diterpenes; D003875:Drug Eruptions / Q000473:pathology*; D006965:Hyperplasia / Q000139:chemically induced / Q000473:pathology; D007202:Indicators and Reagents; D020381:Interleukin-17 / Q000096:biosynthesis; D053759:Interleukin-23 / Q000633:toxicity; D007783:Lactones / Q000008:administration & dosage / Q000494:pharmacology*; D048728:MAP Kinase Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors*; D009955:Ornithine Decarboxylase / Q000096:biosynthesis / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011565:Psoriasis / Q000139:chemically induced / Q000473:pathology; D012867:Skin / Q000473:pathology; D013601:T-Lymphocytes / Q000502:physiology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
C545120:14-(ethylamino)-8,9,16-trihydroxy-3,4-dimethyl-3,4,9,19-tetrahydro-1H-2-benzoxacyclotetradecine-1,7(8H)-dione; D000972:Antineoplastic Agents, Phytogenic; D004224:Diterpenes; D007202:Indicators and Reagents; D020381:Interleukin-17; D053759:Interleukin-23; D007783:Lactones; D047428:Protein Kinase Inhibitors; C011309:mezerein; D003436:Croton Oil; D004139:Dinitrofluorobenzene; D009195:Peroxidase; D019950:Mitogen-Activated Protein Kinase 1; D048728:MAP Kinase Kinase Kinase 1; D009955:Ornithine Decarboxylase; D013755:Tetradecanoylphorbol Acetate