Phospholipase A2s: developing drug targets for atherosclerosis.
The potential for phospholipases as targets for treating atherogenesis has become more prominent over the past year with the publication of the results of Phase 2 clinical trials of two inhibitors of forms of phospholipase A2: darapladib (GSK) which inhibits lipoprotein-associated phospholipase A2 and varespladib (Anthera) an inhibitor of several secreted phospholipase A2s. Although some aspects of their biology overlap, these are distinct targets with different potential for influencing atherogenesis. The background science to these two targets is discussed in this review, noting the balance of data, from human, preclinical species and in vitro that support further development of the inhibitors into Phase 3. Note is taken of another phospholipase A2 (cytosolic) which has been less fully described but for which there has been some interest.
Suckling
Keith
K
GlaxoSmithKline, 291 Knightsfield, Welwyn Garden City, Hertfordshire AL8 7NH, UK. keith@suckling291.freeserve.co.uk
D000085:Acetates / Q000494:pharmacology; D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy*; D001547:Benzaldehydes / Q000494:pharmacology; D015415:Biomarkers; D003600:Cytosol / Q000378:metabolism; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007651:Keto Acids; D008074:Lipoproteins / Q000378:metabolism; D051379:Mice; D010091:Oximes / Q000494:pharmacology; D064801:Phospholipase A2 Inhibitors; D054467:Phospholipases A2 / Q000378:metabolism*; D001713:Biphenyl Compounds; D004048:Diethylamines; D011744:Pyrimidinones; D013440:Sulfides
D000085:Acetates; D001547:Benzaldehydes; D015415:Biomarkers; D004791:Enzyme Inhibitors; D007211:Indoles; D007651:Keto Acids; D008074:Lipoproteins; D010091:Oximes; D064801:Phospholipase A2 Inhibitors; D054467:Phospholipases A2; C117948:varespladib; C529040:darapladib; D001713:Biphenyl Compounds; D004048:Diethylamines; D011744:Pyrimidinones; D013440:Sulfides