Dual 5-lipoxygenase and cyclooxygenase inhibitors

Unangst, P.C., Connor, D.T., Cetenko, W.A., Sorenson, R.J., Kostlan, C.R., Sircar, J.C., Wright, C.D., Schrier, D.J. and Dyer, R.D. (1994) Synthesis and biological evaluation of 5-[[3,5-Bis(l,l-dimethylethyl)-4-hydroxyphenyl]methylene]oxazoles, -thiazoles, and imidazoles Novel dual 5-lipoxygenase and cyclooxygenase inhibitors with antiinflammatory activity. J. Med. Chem. 37 322-328. 

Compounds 111 having structural features of the dual cyclooxygenase (COX)/5-lipooxygenase (5-LO) inhibitor tepoxalin and the 5-LO inhibitor ABT-761 were prepared. Many of these hybrid compounds are potent COX and 5-LO inhibitors two compounds (111, r =McO, R = R" = R = H, R = NH2, R = Me and r = MeO, R = R = Me, R" = R = H, R = Cl) inhibited eicosanoid biosynthesis in an ex vivo assay, but neither improved on the main deficiency of tepoxalin, duration of 5-LO inhibitory activity (99BMCL979). Compounds 111 inhibit the production of arachidonic acid products associated with 5-lipoxygenase and cyclooxygenase and are useful in the treatment of inflammatory disorders (99USP5925769). 

Solid dispersion is defined as one type of method to produce an amorphous compound by incorporating a hydrophobic drug into a hydrophilic carrier (Chiou and Riegelman 1971). It is one of the most studied methods to solubilize and to enhance dissolution rate of biopharmaceutical classification system (BCS) class 2 compounds. For instance, a solid dispersion of ritonavir (Law et al. 2001), ER-3421 (a dual 5-lipoxygenase/cyclooxygenase inhibitor Kushida et al. 2002), was found to have a much higher dissolution rate than the crystalline counterpart and resulted in higher area under curve (AUC) and Cmax in the in vivo study. 

Kushida I, Ichikawa M, Asakawa N (2002) Improvement of dissolution and oral absorption of er-34122, a poorly water-soluble dual 5-lipoxygenase/cyclooxygenase inhibitor with anti-inflammatory activity by preparing solid dispersion. J Pharm Sci 91 258-266 Law D, KriU SL, Schmitt EA, Fort JJ, Qiu YH, Wang WL, Porter WR (2001) Physicochemical considerations in the preparation of amorphous ritonavir-poly(ethylene glycol) 8000 solid dispersions. J Pharm Sci 90 1015—1025... 

Dana A, Ilse Z, Dingermann T, Muller WE, Steinhilber D, Werz O. Hyperforin is a dual inhibitor of cyclooxygenase-1 and 5-lipoxygenase. Biochem Pharmacol 2002 64 1767-1775. 

Tenidap (Figure 8.26) is a dual cyclooxygenase (COX) and 5-lipoxygenase (5-LPO) inhibitor developed as an anti-inflammatory agent. Severe abnormalities in hepatic function were reported in Japanese clinical trials [28]. Although the thiophene is not directly implicated in these findings, the ready activation of this system to potential reactive metabolites may be suggestive of the involvement of this function. 

ML-3000 ((2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine-5-yl)-acetic acid) is a nonantioxidant dual inhibitor of both cyclooxygenase and 5-lipoxygenase. ML-3000 has been compared to indomethacin in a number of experimental models of inflammation. The analgesic effects of ML-3000 have also been assessed in a number of animal models. Phase II studies have shown a wide range of activities, including anti-inflammatory, analgesic, antiplatelet and antiasthmatic properties (Laufer et al., 1994 Chin and Wallace, 1999). 

Inagaki, M. Tsuri, T. Joyama, H. Ono, T. Yamada, K. Kobayashi, M. Hori, Y. Arimura, A. Yasui, K. Ohno, K. Kakudo, S. Koizami, K. Suzuki, R. Kato, M. Kawai, S. Matsumoto, S. Novel Antiarthritic Agents with 1,2-lsothiazolidine-1,1-dioxide (Sultam) Skeleton Cytokine Suppressive Dual Inhibitors of Cyclooxygenase-2 and 5-Lipoxygenase. J. Med. Chem. 2000, 43, 2040-2048. 

Laufer, S. A., Augustin, J., Dannhardt, G., Kiefer, W. (6,7-diaryldihydropyrrolizin-5-yl)acetic acids, a novel class of potent dual inhibitors of both cyclooxygenase and 5-lipoxygenase, J. Med. Chem. 1994, 37, 1894-1897. 

Argentieri DC, Ritchie DM, Ferro MP et al. (1994) Tepoxalin a dual cyclooxygenase/5-lipoxygenase inhibitor of arachi-donic and metabolism with potent anti-inflammatory activity and a favorable gastrointestinal profile. J Pharmacol Exp Ther 271 1399-1408... 

Barbey, S., Goossens, L., Taverne, T., Cornet, J., Choesmel, V, Rouaud, C., Gimeno, G., Yannic-Arnoult, S., Michaux, C., Charlier, C., Houssin, R., Henichart, J. P. Synthesis and activity of a new methox-ytetrahydropyran derivative as dual cyclooxygenase-2/5-lipoxygenase inhibitor. Bioorg. Med. Chem. Lett. 2002, 12, 779-782. 

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