Synthesis and pharmacokinetic properties of novel cPLA2α inhibitors with 1-(carboxyalkylpyrrolyl)-3-aryloxypropan-2-one structure.

Indole-5-carboxylic acids with 3-aryloxy-2­oxopropyl residues in position 1 have been shown to be potent inhibitors of cytosolic phospholipase A2α (cPLA2α), an enzyme involved in the formation of pro-inflammatory lipid mediators. Unfortunately, in animal experiments, only very low plasma concentrations could be achieved after peroral administration of this type of compound. Since insufficient metabolic stability was suspected as the cause, structural modifications were made to optimize this property. These included the conversion of the aromatic into an aliphatic carboxylic acid function as well as the rigidification of the lipophilic structural elements. A selected pyrrole-3-propionic acid was tested for its peroral in vivo bioavailability in mice. However, higher plasma concentrations could not be achieved also with this compound. Using the Caco2 cell permeation assay, substances investigated were found to be very good substrates for gastrointestinal efflux transporters, which explains their poor peroral absorption.

1-(5-Carboxyindazol-1-yl)propan-2-ones as dual inhibitors of cytosolic phospholipase A2α and fatty acid amide hydrolase: bioisosteric replacement of the carboxylic acid moiety.

Indazole-5-carboxylic acids with 3-aryloxy-2-oxopropyl residues in position 1 were previously reported to be potent dual inhibitors of cytosolic phospholipase A2α (cPLA2α) and fatty acid amide hydrolase (FAAH). In continuation of our structure-activity studies on cPLA2α and FAAH inhibitors, a number of derivatives of these substances characterized by bioisosteric replacement of the carboxylic acid functionality by inverse amides, sulfonylamides, carbamates and ureas were prepared. The biological evaluation of the obtained compounds showed that the carboxylic acid functionality of the lead compounds is of special importance for a pronounced inhibition of cPLA2α and FAAH.