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1.
Bioorg Med Chem ; 77: 117110, 2023 01 01.
Article in English | MEDLINE | ID: mdl-36495814

ABSTRACT

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.


Subject(s)
Group IV Phospholipases A2 , Humans , Mice , Animals , Structure-Activity Relationship , Caco-2 Cells , Biological Availability , Biological Transport , Cytosol
2.
J Enzyme Inhib Med Chem ; 31(sup1): 131-140, 2016.
Article in English | MEDLINE | ID: mdl-27162011

ABSTRACT

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.


Subject(s)
Amidohydrolases/antagonists & inhibitors , Carboxylic Acids , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Group IV Phospholipases A2/antagonists & inhibitors , Indazoles/pharmacology , Propane/analogs & derivatives , Amidohydrolases/metabolism , Animals , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Group IV Phospholipases A2/metabolism , Indazoles/chemical synthesis , Indazoles/chemistry , Molecular Structure , Propane/chemical synthesis , Propane/chemistry , Propane/pharmacology , Structure-Activity Relationship , Swine
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