Leukotrienes biosynthesis inhibitors

Farina, P.R., Homon, C.A., Lazer, E.S., and Parks, T.P., Discovery of BIRM 270 a new class of leukotriene biosynthesis inhibitors, in The Search for Anti-Inflammatory Drugs, Case Histories from Concept to Clinic, Merluzzi, V.J. and Adams, ]., Eds., Birkheauser, Boston, 1995, chap. 9. 

M Therien, BJ Eitzsimmons, J Scheigetz, D Macdonald, LY Choo, J Guay, JP Falgueyret, D Riendeau. Justicidin E A new leukotriene biosynthesis inhibitor. Bioorg Medic Chem Lett 3 2063-2066, 1993. 

Ketkar A, Zafar MK, Maddukuri L, Yamanaka K, Baneijee S, Egli M, Choi JY, Lloyd RS, Eofif RL (2013) Leukotriene biosynthesis inhibitor MK886 impedes DNA polymerase activity. Chem Res Toxicol 26(2) 221 232... 

Fig. 4.20. Sites of actions of various leukotriene biosynthesis inhibitors.

Gillard J, Ford-Hutchinson AW, Chan C et al. L-663,536 (MK-866) (3-[l-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl]-2,2-dimethylpropanoic acid), a novel, orally active leukotriene biosynthesis inhibitor. Canadian J Physiol Pharmacol 1989 67 456-464. 

Rouzer CA, Ford-Hutchinson AW, Morton HE, Gillard JW. MK-886, a potent and specific leukotriene biosynthesis inhibitor blocks and reverses the membrane association of 5-lipoxygenase in ionophore-challenged leukocytes. J Biol Chem 1990 265 1436-1442. 

Salmon, J.A. and Garland, G. (1991). Leukotriene antagonists and inhibitors of leukotriene biosynthesis as potential therapeutic agents. Prog. Drug Res. 37, 9-73. 

Wunder A, Anke T, Klostermeyer D, Steglich W (1996) Lactarane Type Sesquiterpenoids as Inhibitors of Leukotriene Biosynthesis and Other, New Metabolites from Submerged Cultures of Lentinellus cochleatus (Pers. ex Fr.) Karst. Z Naturforsch 51c 493... 

Thiol-5-nitrobenzoxazole, the structural material for the preparation of potential enantioselective inhibitors of leukotriene biosynthesis, has been synthesized by condensation of nitro-orf/ioaminophenole with CS2 [506],... 

Koshihara, Y. Neichi, T. Murota, S.I. Lao, A.N. Fujimoto, Y. Tatsuno, T. 1984. Caffeic acid is a selective inhibitor for leukotriene biosynthesis. Biochim. Biophys. Acta. 792 92-97. 

Corey EJ, Shih C, and Cashman JR. (1983). Docosahexaenoic acid is a strong inhibitor of prostaglandin but not leukotriene biosynthesis. Proc. Natl. Acad. Sci. USA 80,3381-3384. 

Boswellinic acids Leukotrienes appear to play a special role as inflammation mediators in the pathogenesis of PBC they also correlate closely with the increase in cholestasis-indicating enzymes. Boswellinic acids are selective non-redox inhibitors of 5-lipoxygen-ase and therefore inhibit leukotriene biosynthesis. So far, they have not been used in PBC treatment. Based on existing pharmacological data, their application should now be considered. 

Chung, K.F. (1995) Leukotriene receptor antagonists and biosynthesis inhibitors ... 

Bell, R.L. er a/. (1995) Optimization of the potertcy and duration of action of N-hydroxyurea 5-lipoxygenase inhibitors./ Pharmacol. Exp. Thor.. 272.724-731. Chung. K.F. (1995) Leukotriene receptor antagonists and biosynthesis inhibitors ... 

Since both (R,R)- and (5,5)-tartaric acid esters are readily available in optically pure form, this method allows the synthesis of both enantiomers of cyclopropanes from a,j8-unsaturated aldehydes in a predictable manner. The method has been successfully applied (see Table 1, entry 6) to the enantioselective synthesis of 5,6-methanoleukotriene A, a stable and selective inhibitor of leukotriene biosynthesis." ... 

It is clear that 5-lipoxygenase (5-LO) [EC 1.13.11.34], through a two-step process, is the enzyme responsible for the production of LTA4. Thus the mechanism of action and, to a lesser extent, the structure of 5-LO have largely influenced the design and discovery of inhibitors of leukotriene biosynthesis. This enzyme has been the subject of intense research since its discovery, as discussed below (Section 5.1), and many inhibitors have been described. 

FLAP inhibitors are a novel class of compounds that inhibit cellular leukotriene biosynthesis without acting directly on 5-LO. Instead, they bind to the 18-kDa membrane FLAP, thus preventing the activation of 5-LO. 

Corey EJ, Cashman JR, Kantner SS, Wright SW (1984) Rationally designed, potent competitive inhibitors of leukotriene biosynthesis. J Am Chem Soc 106 1503-1504... 

A tetrahydropyran that inhibits leukotriene biosynthesis Asymmetric synthesis of2-methyl-tetrahydropyran-4-one by kinetic resolution Part VI - Asymmetric Desymmetrisation of a Diels-Alder Adduct Ifetroban sodium a thromboxane receptor antagonist A laboratory synthesis starting with a Diels-Alder reaction Desymmetrisation of a symmetrical anhydride with a chiral Grignard reagent Laboratory and process routes compared Part VII - Asymmetric Synthesis of A Bicyclic 3-Lactone Lactacystin a naturalproteasome inhibitor... 

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