Synthesis, activity and metabolic stability of propan-2-one substituted tetrazolylalkanoic acids as dual inhibitors of cytosolic phospholipase Aα and fatty acid amide hydrolase.

The serine hydrolases cytosolic phospholipase Aα (cPLAα) and fatty acid amide hydrolase (FAAH) are interesting targets for the development of new anti-inflammatory and analgesic drugs. Structural modifications of a potent dual inhibitor with a propan-2-one substituted tetrazolylpropionic acid moiety led to compounds with also nanomolar activity against both enzymes but better physicochemical properties. The structure-activity relationships showed that the variations had partially divergent effects on the inhibitory activity of the compounds towards cPLAα and FAAH reflecting differences in the binding mode to the enzymes.

Synthesis, activity, metabolic stability and cell permeability of new cytosolic phospholipase Aα inhibitors with 1-indolyl-3-phenoxypropan-2-one structure.

Cytosolic phospholipase Aα (cPLAα), the key enzyme of the arachidonic acid cascade, is considered to be an interesting target for the development of new anti-inflammatory drugs. Potent inhibitors of the enzyme include indole-5-carboxylic acids with propan-2-one residues in position 1 of the indole. Previously, it was found that central pharmacophoric elements of these compounds are their ketone and carboxylic acid groups, which unfortunately are subject to pronounced metabolism by carbonyl reductases and glucuronosyltransferases, respectively.

Tetrazolylpropan-2-ones as inhibitors of fatty acid amide hydrolase: Studies on structure-activity relationships and metabolic stability.

A series of derivatives of 1-(4-octylphenoxy)-3-(2H-tetrazol-2-yl)propan-2-one (3) and 1-(4-octylphenoxy)-3-(1H-tetrazol-1-yl)propan-2-one (4) was synthesized and tested for fatty acid amide hydrolase (FAAH) inhibitory potency and phase I metabolic stability. Introduction of certain substituents like 4-chlorophenyl, 4-methoxycarbonylphenyl and carboxyl in position 5 of the tetrazole ring of 3 led to a significant increase of the metabolic stability of the scissile ketone pharmacophore, while the high activity towards FAAH was not affected markedly. In contrast, substituents in position 5 of the heterocyclic system of 4 did not have a considerable impact on the undesired ketone reduction.