Screening and evaluation of rat kidney aldose reductase inhibitory activity of some pyridazine derivatives

Abstract

Aldose reductase (AR) is an enzyme that catalyzes the conversion of glucose to sorbitol, which is in turn converted to fructose by sorbitol dehydrogenase. The increased glucose flux through this metabolic pathway has been linked to the development of diabetic complications such as neuropathy, nephropathy, retinopathy, and cataract. Inhibitors of AR thus seem to have the potential to prevent or treat diabetic complications. AR inhibitors belong to different chemical classes, one of which comprises pyridazinone analogues. At present, however, side effects and/or insufficient pharmacokinetic profiles have made most of the drug candidates undesirable. We evaluated a series of 2H-pyridazine-3-one and 6-chloropyridazine analogues via an in vitro spectrophotometric assay for their ability to inhibit rat kidney AR. The study showed that the introduction of a pyrazole ring on pyridazinone led to a marked decrease in AR inhibitory potency. Moreover, introduction of an acetic acid side chain on 2H-pyridazine-3-one and 6-chloropyridazine did not improve the AR inhibitory activity, which was an unexpected result. On the basis of preliminary AR inhibitory screening results on 2H-pyridazine-3-one and 6-chloropyridazine derivatives, we embarked on the synthesis of more derivatives to discover more active molecules.