Synthesis of novel phenylacetic acid derivatives with halogenated benzyl subunit and evaluation as aldose reductase inhibitors

• Published in: European journal of pharmaceutical sciences Vol. 27; no. 2; pp. 188 - 193
• Main Authors: Rakowitz, Dietmar, Gmeiner, Andreas, Schröder, Nicole, Matuszczak, Barbara
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier B.V 01-02-2006; Elsevier
• Subjects: Aldehyde Reductase - antagonists & inhibitors; Aldehyde Reductase - isolation & purification; Aldehyde Reductase - metabolism; Aldose reductase; Animals; Benzoates - chemistry; Biological and medical sciences; Cattle; Dose-Response Relationship, Drug; Enzyme inhibitors; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; General pharmacology; Hydrocarbons, Halogenated - chemical synthesis; Hydrocarbons, Halogenated - pharmacology; Inhibitor; Medical sciences; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Phenylacetates - chemical synthesis; Phenylacetates - pharmacology; Structure-Activity Relationship; Substituted phenylacetic acids; Substituted phenylacetic acids; Inhibitor; Enzyme inhibitors; Aldose reductase; Evaluation; Pharmaceutical technology; Acids; Enzyme; Aldehyde reductase; Enzyme inhibitor; Aldose reductase Inhibitor Enzyme inhibitors Substituted phenylacetic acids; Oxidoreductases
• ISSN: 0928-0987; 1879-0720
• DOI: 10.1016/j.ejps.2005.09.006

In the course of our ongoing studies several substituted benzyloxyphenylacetic acids were prepared. Comparison of their aldose reductase inhibition with the biological activity obtained for recently evaluated benzoic acid analogues revealed the critical role of a methylene spacer between the aromatic core and the acidic function. Starting from the most potent derivative (i.e.
5d, IC
50
=
20.9
μM) further structural modifications were performed and their influence on the inhibitory effect was established.