Synthesis of Pyrrolo(3,4-c)pyridine Derivatives Possessing an Acid Group and Their in vitro and in vivo Evaluation as Aldose Reductase Inhibitors.

Abstract Derivatives of [pyrrolo[3,4- c ]pyridin-1,3(2 H )-dion-2-yl] alkanoic acids were prepared and their in vitro aldose reductase inhibitory activity was tested on rat lens enzyme. The acetic derivatives 2, 5 and 15a–d proved to be much more potent inhibitors than the propionic derivatives, 7 and 16a–d , and the iso-propionic derivatives, 3 and 6 . The presence of a second planar aromatic area in the benzoyl derivatives 15a–d did not result in any increase in activity. Two of the most active compounds in vitro ( 2 and 5 ) were also evaluated in vivo as inhibitors of glutathione lens depletion in galactosemic rats. None of the compounds was found to be active in maintaining the rat lens glutathione level, suggesting possible problems of ocular bioavailability and metabolism. The aldose reductase inhibitory activity of compounds 2 and 15d was also discussed by taking into account their conformational and electronic characteristics evaluated by means of theoretical calculations.