Group VIA calcium-independent phospholipase A2 (GVIA iPLA2) has recently emerged as a novel pharmaceutical target. We have now explored the structure−activity relationship between fluoroketones and GVIA iPLA2 inhibition. The presence of a naphthyl group proved to be of paramount importance. 1,1,1-Trifluoro-6-(naphthalen-2-yl)hexan-2-one (FKGK18) is the most potent inhibitor of GVIA iPLA2 (XI(50) = 0.0002) ever reported. Being 195 and >455 times more potent for GVIA iPLA2 than for GIVA cPLA2 and GV sPLA2, respectively, makes it a valuable tool to explore the role of GVIA iPLA2 in cells and in vivo models. 1,1,1,2,2,3,3-Heptafluoro-8-(naphthalene-2-yl)octan-4-one inhibited GVIA iPLA2 with a XI(50) value of 0.001 while inhibiting the other intracellular GIVA cPLA2 and GV sPLA2 at least 90 times less potently. Hexa- and octafluoro ketones were also found to be potent inhibitors of GVIA iPLA2; however, they are not selective.

The resolution of 2-amino alcohols protected by urethane-type groups either via porcine pancreatic lipase (PPL) hydrolysis of the corresponding racemic acetates or via PPL catalyzed transesterification of racemic alcohols was studied. In both cases, Boc protecting group led to better chemical yields and enantiopurities than Z and Fmoc protecting groups. Furthermore, a simple and efficient method for the synthesis of the medicinally interesting optically pure (R)-2-aminohexadecanol was developed. 

Importance of the field: The various phospholipase A2 (PLA2) types have been implicated in diverse kinds of lipid signaling and inflammatory diseases. Rheumatoid arthritis, lung inflammation, neurological disorders, such as multiple sclerosis, cardiovascular diseases, including atherosclerosis, and cancer are included among the diseases where PLA2 enzymes are involved. Thus, there is a great interest in developing potent and selective PLA2 inhibitors and some of them have entered clinical trials. Areas covered in this review: This review article discusses the role of each PLA2 class in inflammatory diseases and the advances in the development of inhibitors presented in patent literature from January 2004 to May 2009. What the reader will gain: PLA2s cluster in four main types: secreted sPLA2, cytosolic cPLA2, Ca2+-independent iPLA2 and lipoprotein-associated LpPLA2. Each of those types has been implicated in diverse kinds of inflammatory diseases. Readers will rapidly gain an overview of the various PLA2 inhibitors reported in the patent literature in the past 5 years. Furthermore, the readers will learn the difficulties related to the development of PLA2 inhibitors as new drugs and also the different companies and research groups that are the main players in the field. Take home message: Although the role of each PLA2 is not yet distinct in different diseases, the development and future use of different PLA2 inhibitors to treat human disease seems very promising.