Arachidonic acid cascade inhibitors

A series of 4-arylpyrimidines that arc amine substituted at pyrimidine C-2 was prepared. FK360 was most effective from this group on both arachidonate-induced cerebral oedema in rats and as an in vitro inhibitor of lipid peroxidation. The authors link effects of FK360 to the arachidonic acid cascade (Kuno et al., 1992). This is an unusual structure. 

Stabler I, Kapui Z, Ambrus J L1994 Study on the mechanisms of action of sodium meclofenamic acid (meclomen) a double inhibitor" of the arachidonic acid cascade. Journal of Medicine 25 371-382 Stillman M, Schlesinger P 1990 Nonsteroidal antiinflammatory drugs nephrotoxicity. Archives of Internal Medicine 150 268-270... 

Prostaglandins have been another disappointment. They have orphan drug status in a number of applications, but developments have been slow. Our understanding of the arachidonic acid cascade, the biosynthetic route to prostaglandins, has led to advances in the development of prostaglandin inhibitors (e.g. the nonsteroid anti-inflammatories). Prostaglandin analogues, on the other hand, have at present only a handful of indications (Table 43.4). 

Tepoxalin is a potent inhibitor of both the cyclcooxygenase and lipoxygenase pathways of the arachidonic acid cascade. In a facile and more environmentally friendly synthesis, condensation between methoxyphenyl-hydrazine and the bis-ketone with a pendant hydroxamic acid group at the end of the molecule delivered tepoxalin in 70% yield. 

Another important aspect of the inflammatory cascade is arachidonic acid metabolism, leading to the synthesis of the proinflammatory prostaglandins and leukotrienes. Through the formation of Upocortin, an inhibitor of phospholipase A2, glucocorticoids depress the release of arachidonic acid from phospholipids and hence the production of arachidonic acid metabolites. 

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