(+/-)-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.
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.
Cai
X
X
CytoMed, Inc., 840 Memorial Drive, Cambridge, Massachusetts 02139, and Department of Chemistry, University of Virginia, Charlottesville, Virginia 22903, USA.
Scannell
R T
RT
Yaeger
D
D
Hussoin
M S
MS
Killian
D B
DB
Qian
C
C
Eckman
J
J
Hwang
S B
SB
Libertine-Garahan
L
L
Yeh
C G
CG
Ip
S H
SH
Shen
T Y
TY
D000818:Animals; D016718:Arachidonic Acid / Q000633:toxicity; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D016466:CHO Cells; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D004353:Drug Evaluation, Preclinical; D004487:Edema / Q000139:chemically induced; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006400:Hematocrit; D006801:Humans; D007975:Leukotriene B4 / Q000096:biosynthesis / Q000097:blood; D016859:Lipoxygenase Inhibitors; D051379:Mice; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D051381:Rats; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D013329:Structure-Activity Relationship; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity; D014407:Tumor Cells, Cultured; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D004791:Enzyme Inhibitors; D005663:Furans; D016859:Lipoxygenase Inhibitors; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; D007975:Leukotriene B4; D016718:Arachidonic Acid; C112433:CMI 392; D014508:Urea; D013755:Tetradecanoylphorbol Acetate