A series of new 1,4-dihydro-1,2,4-triazolo[4,3-]quinoxaline-1,4-diones has been prepared. These compounds were tested as inhibitors of antigen-induced release of histamine (AIR) in vitro from rat peritoneal mast cells (RMC) and as inhibitors of IgE-mediated rat passive cutaneous anaphylaxis (PCA). Most of this new class of antiallergic agents showed good activity in the RMC and PCA tests. The most potent compound, 2-acetyl-7-chloro-5-n-propyl-1,2,4-triazolo[4,3-a]quinoxaline-1,4-dione (1x), with an I50 value of 0.1 microM, is 30 times more potent than disodium cromoglycate (DSCG) in the RMC assay.
Leukotriene B4 is a potent activator for polymorphonuclear (PMN) 1eukocytes.l It causes increased chemotactic and chemokinetic migration, aggregation, degranulation, lysosomal enzymes release, and free radical release. Because of these biological activities, LTB4 may play an important role in inflammatory diseases in which elevated levels of LTB4 have been detected, such as inflammatory bowel disease, rheumatoid arthritis, and psoriasis. The effects Of LTB4 are mediated through high-and low-affinity receptors on the surface of leukocytes. Since many receptor antagonists of other potent mediators have already demonstrated therapeutic value in man, the search for LTB4 receptor antagonists represents a rational therapeutic approach to inflammatory diseases. In this communication, we report the discovery of a potent new LTB4 antagonist.Several LTB4 receptor antagonists with a variety of biological activities have been reported in the literature. For example, SC-41930 (11, a well-studied LTB4 antagonist with multiple biological activities, exhibits only moderate binding affinity (ICs0 = 300 nM) to human neutrophils.2 Upjohn reported a series of LTB4 structure-based antagonists with ICs0 values ranging from 80 to 400 nM, but most of the compounds appear to exhibit mixed agonist/ antagonist a~tivity.~ Recently, Eli Lilly has reported LY 223982 (2) as a potent LTB4 antagonist with an ICs0 of 12 nM against human PMN LTB4 receptor^.^ ONO-LB-457 (3), which has a similar but slightly modified structure, is (1) For a recent review and relevent references, see: Kingsbury, W.; Daines, R.; Gleason, J.
The synthesis of a series of novel substituted hydroxamates has been described along with their profile of inhibitory activity against 5-lipoxygenase, 12-lipoxygenase, and cyclooxygenase enzymes. The structure--activity relationship suggests that future molecules could be designed to specifically inhibit one or more of these enzymes since there were definite differences in structure--activity relationships for these different enzymes. A representative number of these compounds have been tested in vivo and found to possess potent oral activity in a systemic anaphylaxis model mediated by leukotrienes and topical activity in an arachidonic acid induced inflammation model. One of these molecules, compound 20, demonstrated that a leukotriene antagonist pharmacophore can be modified such that it contains both antagonist activity and 5-lipoxygenase inhibitory activity.
The synthesis of a series of [1,4]benzoxazine-2,3-diones and a new class of compounds, benzobisoxazinetetrones, is described. These compounds were evaluated for their effect in the rat mast cell (RMC) test passively sensitized in vitro with rat antiovalbumin serum and for their effect in inhibitory passive cutaneous anaphylaxis (PCA) in the rat. Some of these compounds are of the same potency level as disodium cromglycate in the RMC test and some are effective orally in PCA.
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