In addition to having desirable inhibitory effects on inflammation, anaphylaxis, and smooth muscle contraction, PDE-IV inhibitors also produce undesirable side effects including nausea and vomiting. In general, compounds that inhibit PDE-IV also potently displace [3H]rolipram from a high-affinity binding site in rat cortex. While this binding site has not been identified, it has been proposed to be an allosteric binding site on the PDE-IV enzyme. Preliminary studies have suggested that the emetic potency of PDE-IV inhibitors is correlated with affinity for the brain rolipram binding site rather than potency at inhibiting PDE-IV enzyme activity. Efforts to eliminate the emetic potential of PDE-IV inhibitors were directed toward developing compounds with decreased [3H]rolipram binding affinity while retaining PDE-IV potency. Thus, a novel series of 4-(3-alkoxy-4-methoxyphenyl)benzoic acids and their corresponding carboxamides were prepared and evaluated for their PDE-IV inhibitory and rolipram binding site properties. Modification of the catechol ether moiety led to phenylbutoxy and phenylpentoxy analogues that provided the desired activity profile. Specifically, 4-[3-(5-phenylpentoxy)-4-methoxyphenyl]-2-methylbenzoic acid, 18, was found to exhibit potent PDE-IV inhibitory activity (IC50 0.41 microM) and possessed 400 times weaker activity than rolipram for the [3H]rolipram binding site. In vivo, compound 18 was efficacious in the guinea pig aerosolized antigen induced airway obstruction assay (ED50 8.8 mg/kg, po) and demonstrated a significant reduction in emetic side effects (ferret, 20% emesis at 30 mg/kg, po).
Current treatments for inflammatory diseases such as rheumatoid arthritis (RA), psoriasis, and inflammatory bowel disease (IBD) are not satisfactory.1 The sideeffect profiles of steroids and immunosuppressants limit their long-term use in all inflammatory conditions, while in arthritis, NS AIDS offer only palliative relief and do not halt disease progression.2 Clearly, a novel agent with decreased side effects that suppressed tissue damage would represent a major advance in the treatment of debilitating inflammatory disease. Conceptually, one novel approach would be to inhibit the migration of leukocytes into the inflamed tissue and thereby block delivery by these cells of degradative enzymes, reactive oxygen species, and cytokines.The migration of leukocytes in vivo is regulated by chemotactic factors that control both directional migration of cells (chemotaxis) and upregulation of cell surface adhesion molecules mediating cell-cell contact events required for cellular movement. One such factor is leukotriene B* (LTB4) produced by the 5-lipoxygenase
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