CMI-392是一种双重5-lipoxygenese抑制剂和血小板活化因子(PAF)受体拮抗剂，IC50值分别为100和10nM。
CMI-392 is a dual 5-lipoxygenese inhibitor and platelet-activating factor (PAF) receptor antagonist with IC50s of 100 and 10 nM, respectively.
Topical treatment of CMI-392 in the acute and chronic TPA models result in a significant decrease of ear weight, inflammatory cell infiltration, and histological examination. The ED50 for PAF-induced mouse hemoconcentration and arachidonic acid-induced mouse ear edema are 2.2 and 1.8 mg/kg, respectively[1].
[1]. Cai X, et al. (+/-)-trans-2-[3-methoxy-4-(4-chlorophenylthioethoxy)-5-(N-methyl-N- hydroxyureidyl)methylphenyl]-5-(3,4, 5-trimethoxyphenyl)tetrahydrofuran (CMI-392), a potent dual 5-lipoxygenase inhibitor and platelet-activating factor receptor antagonist. J Med Chem. 1998 May 21;41(11):1970-9.
Kinase experiment: | 5-lipoxygenese activity in cell lysate is determined as follows: 0.1 mL reactions consisting of buffer, test compound (CMI-392 in DMSO), and an amount of cell lysate that will convert 15% of [14C]AA substrate mix to oxygenated products are incubated (20 min, room temperature). A substrate mix containing [14C]AA is added and incubated further (5 min, 37°C). The reaction is terminated by adding 0.2 mL of an organic extraction solution containing triphenylphosphine, followed by microcentrifugation. The organic phase (50 μL) is spotted onto silica gel TLC plates. The plates are developed in ethyl ether/acetic acid (100:0.1) (25 min, room temperature). Plates are exposed to film for 36 h. The film is developed and scanned using a densitometer, and the peak areas of AA and its products are calculated[1]. |
Animal experiment: | Mice: Acute TPA-induced ear edema in mice is determined by topically applying TPA to the ears of mice. Mice are sacrificed after 6 h and the ear punch biopsies are weighed. Chronic TPA-induced ear edema in mice is determined by topically applying TPA once a day every 2 days for a total of 10 days. CMI-392 is topically administered twice daily on the last 3 days of the experiment. Mice are then sacrificed and the ear punch biopsies are weighed. Biopsies are homogenized and MPO content is determined via spectrophotometric assay[1]. |
参考文献: [1]. Cai X, et al. (+/-)-trans-2-[3-methoxy-4-(4-chlorophenylthioethoxy)-5-(N-methyl-N- hydroxyureidyl)methylphenyl]-5-(3,4, 5-trimethoxyphenyl)tetrahydrofuran (CMI-392), a potent dual 5-lipoxygenase inhibitor and platelet-activating factor receptor antagonist. J Med Chem. 1998 May 21;41(11):1970-9. | |
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