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Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a serine lipase that is associated with low density lipoprotein (LDL) in human plasma. Substrates include oxidised phosphatidylcholine (PC), which is hydrolysed by Lp-PLA2 to lyso-PC and oxidised fatty acids. Both products are bioactive and proinflammatory, and implicated in monocyte infiltration into the developing plaque, deposition of foam cells, and plaque progression and instability. Lp-PLA2 has recently been shown to be a risk factor for coronary events in previously asymptomatic, hypercholesterolaemic men. A series of azetidinones was designed as potent and selective inhibitors of this enzyme; SB-222657 inhibited release of the chemotactic cleavage products from oxidised LDL, and SB-244323 reduced atherosclerotic plaque development in a 3 month rabbit study. A series of pyrimidones has been designed from a screening hit, and nanomolar inhibitors identified. Oral efficacy in inhibiting plasma Lp-PLA2 in rabbits has been demonstrated with a variety of structural classes.

A mild, base mediated conversion of an azetidin-2-one to the [1,4]-diazapinedione system is reported and a putative mechanistic pathway is proposed.

The synthesis of analogues of SB-253514, a novel natural product derived inhibitor of lipoprotein associated phospholipase A2 (Lp-PLA2), is described together with their ability to inhibit Lp-PLA2.

The key step in the synthesis of L-3,5-dibromo-3′-[6-oxo-1,6-dihydropyridazin-3-yl)methyl]-thyronine, SK&F L-94901 (1), a novel, selective, and potent thyromimetic, is the formation of the hindered diaryl ether moiety. This paper describes an investigation into the formation of the required diaryl ether by copper-catalysed reaction both of symmetrical iodonium salts (2a) and (10) and mixed iodonium salts (2b–e) with protected dibromotyrosine (5). The importance of the counter-ion of the iodonium salt is discussed. This work is extended to a large-scale synthesis of SK&F L-94901 (1).