ABSTRACT
Histamine is a primary mediator in allergic response and acts in concert with other agents to impact disease progression. Respiratory disorders such as asthma, rhinitis and dermatological conditions such as urticaria involve histamine along with other mediators. An antihistamine that possesses an additional property of counteracting the effects mediated by these other mediators should offer some therapeutic benefit over a selective antihistaminergic agent.
Subject(s)
Histamine H1 Antagonists/pharmacology , Animals , Bradykinin B2 Receptor Antagonists , Histamine H1 Antagonists/chemistry , Humans , Leukotrienes/metabolism , Receptor, Bradykinin B2/metabolism , Receptors, Histamine/metabolism , Receptors, Tachykinin/antagonists & inhibitors , Receptors, Tachykinin/metabolism , Receptors, Thromboxane A2, Prostaglandin H2/antagonists & inhibitors , Receptors, Thromboxane A2, Prostaglandin H2/metabolismABSTRACT
Leukotrienes (LTs) and platelet-activating factor (PAF) are important mediators of inflammation and allergy. LDP-392, a novel dual PAF receptor antagonist and 5-lipoxygenase (5-LO) inhibitor, has been identified. LDP-392 is 17.9-fold more potent than zileuton (5-LO inhibitor) in the RBL cytosolic 5-LO assay, and equally potent as MK 287 (PAF receptor antagonist) in the human platelet PAF receptor binding assay. The in vivo dual activities of LDP-392 were confirmed by measuring the inhibition of ex vivo LTB(4)production in rats and PAF-induced hemoconcentration in mice. Intravenous administration of LDP-392 demonstrated greater inhibition than zileuton, BN 50739 or MK 287 on arachidonic acid-induced ear edema and protected mice from LPS-induced lethality. Topical administration of LDP-392, in a dose-dependent manner, inhibited TPA-induced ear edema in mice and UVB-induced erythema in guinea-pigs. These data suggest that LDP-392, as a dual PAF receptor antagonist and 5-LO inhibitor, may be of greater clinical effectiveness.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Furans/pharmacology , Lipoxygenase Inhibitors , Lipoxygenase Inhibitors/pharmacology , Platelet Activating Factor/metabolism , Platelet Membrane Glycoproteins/antagonists & inhibitors , Receptors, Cell Surface , Receptors, G-Protein-Coupled , Urea/pharmacology , Animals , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Arachidonate 5-Lipoxygenase/metabolism , Dose-Response Relationship, Drug , Edema/drug therapy , Erythema/drug therapy , Female , Guinea Pigs , Humans , Lipoxygenase Inhibitors/therapeutic use , Mice , Platelet Membrane Glycoproteins/metabolism , Rats , Urea/analogs & derivativesABSTRACT
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.
