(±)-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

Abstract

By incorporating an N-hydroxyurea functionality onto diaryltetrahydrofurans, a novel series of compounds was investigated as dual 5-lipoxygenese (5-LO) inhibitor and platelet-activating factor (PAF) receptor antagonist. These dual functional compounds were evaluated in vitro for 5-LO inhibition in RBL cell extracts and human whole blood, and PAF receptor antagonism in a receptor binding assay. PAF-induced hemoconcentration and arachidonic acid- and TPA-induced ear edema in mice were used to determine in vivo activities. The structure-activity relationship analysis to define a preclinical lead is presented. (+/-)-trans-2-[3-methoxy-4-(4-chlorophenylthioethoxy)-5-(N-methyl- N-h ydroxyureidyl)methylphenyl]-5-(3,4, 5-trimethoxyphenyl)tetrahydrofuran (40, CMI-392) was selected for further study. In the arachidonic acid-induced mouse ear edema model, 40 was more potent than either zileuton (a 5-LO inhibitor) or BN 50739 (a PAF receptor antagonist), and it demonstrated the same inhibitory effect as a physical combination of the latter two agents. These results suggest that a single compound which both inhibits leukotriene synthesis and blocks PAF receptor binding may provide therapeutic advantages over single-acting agents. The clinical development of compound 40 is in progress.

Síntese e avaliação de derivados furânicos, tetraidrofurânicos e pirrólicos com potencial atividade tripanocida

“…A ciclização de 1,4-diaril-1,4-diidroxílico 30 foi realizada na presença de ácido trifluoroacético em clorofórmio, conduzindo a formação do correspondente 2,5-diariltetraidrofurano (31) desejado, conforme descrito por Bernardes, 2002, mostrado no esquema 15 (BERNARDES, 2002CAI, 1998). …”