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Document Figure 14 (Continued) Page 426 fenic acid and dexamethasone [91]. A patent report from the National Institutes of Health describes a method of treating diseases associated with elevated levels of interleukin-1. Rosenthal, as the inventor of this patent, describes a method for inhibiting the release of IL-1 from IL-1-producing cells by administering a therapeutically effective amount of an aromatic diamidine (WO9115201-A). http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_426.html (1 of 2) [4/5/2004 5:50:41 PM]
Document Page 427 These aromatic diamidines inhibit IL-1 production and also block IL-6 and TNF. Imidazoline blocks IL- 1 and TNF and is less toxic to the cell with an in vitro LD 50 >>10 -4. Examples of these compounds are 1,5-bis(4-amidophenoxy) pentane (pentamidine), in the form of pentamidine isothionate, and an imidazoline in the form of 1,5-di(4-imidazolinophenoxy)pentane. Tricycli- cylidene-acetic acid [92] and its 2-chloro derivative [93] were found to be inhibitors of IL-1 release, claiming clinical improvement in patients with psoriasis, periodontal disease, and Alzheimer's disease. In vitro this compound blocks the synthesis of prostaglandins and inhibits the release of IL-1α and IL-1β from human monocytes and murine macrophages. Probucol, a hypocholesterolemic drug that possesses antioxidant activity, inhibits the ex vivo release of IL-1 from LPS-stimulated macrophages of mice pretreated orally with 100 mg/kg/day of this compound [94,95]. This compound has been shown to inhibit LPS-induced zinc-lowering effect, is cited as direct evidence for the inhibition of IL-1 release, and may be useful candidate for the treatment of atherosclerosis [95,96]. An amino-dithiol-one derivative (RP 54745) blocked the proliferative action of IL-1β on murine thymocytes in vitro and also inhibited the production of IL-1 in mouse peritoneal macrophages in vitro and in vivo. The compound RP 54745 selectively inhibited the expression of IL- 1α and IL-1β mRNA while TNFα mRNA was unaffected [97, 98]. Administration of a cocktail containing eicosapentenoic acid and docosahexenoic acid to volunteers for up to 6 weeks, resulted in a significant depression in IL-1β (61%), IL-1α (39%), and TNF (40%) synthesis. These levels returned to normal after a few weeks [99]. In vitro studies indicate that Pentoxifylline can block the effects of IL-1 and TNF on neutrophils [100]. It is a phosphodiesterase (PDE) inhibitor that causes increased capillary blood flow by decreasing blood viscocity and is used clinically in chronic occlusive arterial disease of the limbs with intermittent claudication. Denbufylline, a closely related xanthine, has been patented as a functional inhibitor of cytokines and exhibits a similar profile to Pentoxifylline [101]. Romazarit (Ro-31-3948) derived from oxazole and isoxazole propionic acids has been shown to block IL- 1-induced activation of human fibroblasts in vitro and in animal models reduces inflammation [102,103,104]. By using a spontaneous autoimmune MRL/lpr mouse model, a significant efficacy was shown [105]. Two-dimensional structures of some of these molecules are shown in Figure 14. Even though the above mentioned small molecules exhibit IL-1 inhibition none of them were discovered based on defined functional or structural aspects. An understanding of the three-dimensional structure of IL-1s and their receptors, by themselves or in complexes, will form a very strong foundation for structure-based design of more specific and potent IL-1-based immunomodulators. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_427.html [4/5/2004 5:50:49 PM]
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