Phospholipase inhibitor

Pseudopterosin A is a member of a group of marine natural products which show potent antiinflammatory properties, but which are not prostaglandin biosynthesis inhibitors. Structurally similar to phosphatidyl inositol, they may function as phospholipase inhibitors, and, as such, may be the forerunners of a new class of therapeutic agents. 

A common problem with gap junction measurements is a rundown of gj in these preparations, for example in neonatal rat heart cells Schmilinsky-Fluri et al. [1990] found a decrease in g, of 16.4% in 6 min which could be antagonized by addition of a phospholipase inhibitor, 20 pmol/l bromophenacyl bromide, to 1.8% within 6 min. They suggested that endogenous arachidonic acid is involved in spontaneous uncoupling. Others favored a washout of ATP and cyclic nucleotides as a possible cause and prevented their preparations from spontaneous uncoupling by addition of ATP, GTP or cAMP to the pipette solution [Miiller et al., 1997a, b]. 

The highly substituted indole, ecopladib (82), which shares many structural elements with the phospholipase inhibitor varespladib (37), shows similar biological activity. Alkylation of hydroxy benzoate (72) with the dimethyl acetal from bromoacetaldehyde (73) affords the ether (74). Acid-catalyzed reaction of this intermediate with 2-methyl-5-chloroindole (75) in the presence of triethylsilane leads in effect to condensation of the acetal with the activated 3 position on the indole ring to afford 76. The nature of the reduction of the aldehyde carbon is not immediately apparent. Alkylation of the anion on nitrogen from reaction of the indole with sodium hydride and bromodiphenylmethane then adds the third... 

REDUCTASE INHIBITORS DOPA-DECARBOXYLASE INHIBITORS DOPAMINE P-HYDROXYLASE INHIBITORS ENDOPEPTIDASE INHIBITORS HMG-COA REDUCTASE INHIBITORS NEUTRAL ENDOPEPTIDASE INHIBITORS NITRIC OXIDE SYNTHASE INHIBITORS PHOSPHOLIPASE INHIBITORS 5a-REDUCTASE INHIBITORS REVERSE TRANSCRIPTASE INHIBITORS THROMBOXANE SYNTHASE... 

For the reasons given above, agents that interfere with leukotriene synthesis or actions, are of great interest in relation to limiting inflammatory reactions. The sites amenable to pharmacological manipulation include (I) the upstream inhibition of arachidonic acid production from phospholipids (which is a rate-limiting step see PHOSPHOLIPASE inhibitors) (2) the inactivation of five-... 

Phospholine Iodide" - ecothiopate iodide. PHOSPHOLIPASE INHIBITORS act at sites on phospholipases, a large group of enzymes with many roles. There are two main groups of enzyme of particular interest in relation to receptor signalling, which makes them important drug targets phospholipase Aj and phospholipase C. These will be discussed in turn. 

Makhej a AN, B ailey JM. A platelet phospholipase inhibitor from the medicinal herb feverfew (Tanacetum parthenium). Prostaglandins LeukotMed 1982 8 653-660. 

Glucocorticoids (e.g., cortisol) inhibit phospholipase A2 activity by induction of synthesis of a phospholipase inhibitor protein, which partly explains their antiinflammatory effects. 

Recent developments in this important reaction have helped to reveal the relationship between 2D and 3D stereochemistry. The synthesis of the phospholipase inhibitor cinatrin B 207 illustrates a serious stereochemical problem.39 Cinatrins have spiro-fused lactones. Each ring contains chiral centres and the spiro C-atom is also chiral. It is very difficult to relate stereochemistry between such orthogonal rings. The second lactone might be added by cyclisation onto an alkene such as 208 and that could arise from allylation of an enolate 209. Clearly some protection will be needed. 

Phospholipase inhibitors Thromboxane synthetase inhibitors Prostacyclin... 

Hinder, M. (1998). Investigation on the effect of experimental phospholipase inhibitors on the formyl-methionyl-leucyl-phenylalanine-stimulated chemotaxis of human leukocytes in vitro. Arzneim.-Forsch./Drug Res. 48, 77-81. 

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