1‐(3‐Biaryloxy‐2‐oxopropyl)indole‐5‐carboxylic Acids and Related Compounds as Dual Inhibitors of Human Cytosolic Phospholipase A₂α and Fatty Acid Amide Hydrolase

Abstract

Cytosolic phospholipase A2α (cPLA2α) and fatty acid amide hydrolase (FAAH) are enzymes that have emerged as attractive targets for the development of analgesic and anti-inflammatory drugs. We recently reported that 1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid (5) is a dual inhibitor of cPLA2α and FAAH. Structure-activity relationship studies revealed that substituents at the indole 3- and 5-positions and replacement of the indole scaffold of this compound by other heterocycles strongly influences the inhibitory potency against cPLA2α and FAAH, respectively. Herein we report the effect of variation of the 4-octyl residue of 5 and an exchange of its carboxylic acid moiety by some bioisosteric functional groups. Several of the compounds assayed were favorably active against both enzymes, and could therefore represent agents with improved analgesic and anti-inflammatory qualities in comparison with selective cPLA2 α and FAAH inhibitors.

Anti‐Inflammatory Property of n‐Hexadecanoic Acid: Structural Evidence and Kinetic Assessment

“…Fatty acid derivatives of bee venom and sea weeds in micro molar concentrations caused >90% inhibition of PLA 2 (11). Fatty acid tricarbonyl derivatives were found to be inhibitors of human non‐pancreatic cPLA 2 α (12). Thielocin B3 is a potent naturally occurring inhibitor of human nonpancreatic sPLA 2 (13).…”

Inhibition of benzalkonium chloride-induced skin inflammation in mice by an indol-1-ylpropan-2-one inhibitor of cytosolic phospholipase A2α

“…Like cPLA 2 α, these two enzymes possess a catalytic serine in the active site and they hydrolytically release arachidonic acid from their substrates. Furthermore, several common inhibitors of cPLA 2 α, FAAH and MAGL are known, such as arachidonyl trifluoromethyl ketone and MAFP 31,32,45 . The inactivity of compound 1 against FAAH and MAGL, which also play important roles in inflammatory processes, 48 provides further evidence for the selectivity of our cPLA 2 α inhibitor.…”

“…At the highest test concentration of 10 μmol L −1 no inhibition of the two enzymes by compound 1 was observed. In contrast, with IC 50 values of 0·025 and 0·062 μmol L −1 , respectively, the nonspecific cPLA 2 α inhibitor methyl arachidonyl fluorophosphonate (MAFP) inhibited these two enzymes with high potency 32,45 …”

“…In contrast, with IC 50 values of 0AE025 and 0AE062 lmol L )1 , respectively, the nonspecific cPLA 2 a inhibitor methyl arachidonyl fluorophosphonate (MAFP) inhibited these two enzymes with high potency. 32,45 Discussion cPLA 2 a plays a key role in the initial formation of inflammatory lipid mediators such as prostaglandins, leukotrienes and PAF and is therefore supposed to be an important target for the treatment of ICD and other inflammatory diseases.…”

Inhibitors of the Arachidonic Acid Cascade: Interfering with Multiple Pathways

“…The subsequent optimization led to a potent inhibitor 6 (fig. ) of both enzymes through the variation of a heterocycle and the substitution pattern .…”