Regulation of phospholipase A2 enzymes: selective inhibitors and their pharmacological potential.
The area of PLA2 research has grown immensely over the past 20 years. There is a better understanding of the kinetics, or factors that affect the kinetics, of the different forms of PLA2. New forms of PLA2 are being discovered, such as the cPLA2, which fit the role of an intracellularly regulated enzyme. Multiple forms of PLA2 tend to complicate the elucidation of the cellular mechanisms that regulate AA release and the subsequent eicosanoid production. Because of the factors that affect PLA2 kinetics and the unknown nature of the PLA2 that regulates AA release (there may be more than one), it has been difficult to design or isolate specific inhibitors. This review discussed selected classes of inhibitors because these have generated the most intense research in the field. There is a multitude of structurally diverse compounds reported in the literature that have been reported to be inhibitors of PLA2 in vitro and some have been reported to have anti-inflammatory activity (Wilkerson, 1990; Connolly and Robinson, 1993a). It is clear from a brief survey of the literature that the bulk of PLA2 inhibitors have topical anti-inflammatory activity. This may be due to the nature of these inhibitors: because they are hydrophobic they may be more readily absorbed in the skin whereas when given orally they may not be absorbed. To data, manoalide has been clinically evaluated in man and a new Bristol-Myers Squibb retenoid derivative may enter clinical trials for psoriasis (BMS-181162 (XVI)); however, there are no PLA2 inhibitors on the market or significantly advanced in clinical development (Table III). This indicates the lack of understanding of this enzyme for the development of relevant inhibitors, which is related to the lack of understanding of the relevant PLA2 that regulates AA release and eicosanoid biosynthesis. The concept of regulation of eicosanoid biosynthesis by PLA2 inhibition and decreased AA availability still remains a viable therapeutic approach for the treatment of inflammatory diseases. The proof of this concept has not been obtained because of the complex nature of PLA2 and the multiple forms of PLA2 in the cell. Clinical results with cyclooxygenase inhibitors and recent clinical results with inhibitor of 5-lipoxygenase demonstrate that if inhibition of PLA2 results in reduction in both lipid mediators, a good anti-inflammatory compound should result. The added advantage of PLA2 inhibitors would be the reduction of PAF levels; however, the clinical results with potent and specific PAF antagonists has been less encouraging about the potential benefits of reduction in PAF levels.(ABSTRACT TRUNCATED AT 400 WORDS)
Glaser
K B
KB
Wyeth-Ayerst Research/Princeton, New Jersey 08543, USA.
D000818:Animals; D017302:Annexins / Q000494:pharmacology; D016373:DNA, Antisense; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008954:Models, Biological; D010741:Phospholipases A / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D054467:Phospholipases A2; D010743:Phospholipids / Q000494:pharmacology
D017302:Annexins; D016373:DNA, Antisense; D004791:Enzyme Inhibitors; D010743:Phospholipids; D010741:Phospholipases A; D054467:Phospholipases A2