Discovery of a novel benzothiadiazine-based selective aldose reductase inhibitor as potential therapy for diabetic peripheral neuropathy.

Aldose reductase2 (ALR2), an activated enzyme in polyol pathway by hyperglycemia, has long been recognized as one of the most promising targets for diabetic complications especially in diabetic peripheral neuropathy (DPN). However, lots of ALR2 inhibitors showed serious sideeffects due to poor selectivity over aldehyde reductase (ALR1). Herein, we described the discovery of a series of benzothiadiazine acetic acid derivatives as potent and selective inhibitors against ALR2 and evaluation of their anti-DPN activities in vivo. Compound 15c carrying carbonyl group at the 3-position of thiadiazine ring showed high potent inhibition against ALR2 (IC50 = 33.19 nM) and about 16109-fold selectivity for ALR2 over ALR1. Cytotoxicity assays ensured the primary biosafety of 15c. Further pharmacokinetic assay in rats indicated 15c had a good pharmacokinetic feature (T1/2 = 5.60 h, AUC(0-t) = 598.57±216.5 μg/mL*h), which was superior to Epalrestat (T1/2 = 2.23 h, AUC(0-t) = 20.43±3.7 μg/mL*h). Finally, in streptozotocin (STZ)-induced diabetic rat model, 15c significantly increased the nerve conduction velocities (NCVs) of impaired sensory and motor nerve, achieved potent inhibition of D-sorbitol production in the sciatic nerves, and significantly increased the paw withdrawal mechanical threshold (PWMT). Combined the above investigations, we proposed that 15c might represent a promising lead compound for discovery of anti-diabetic peripheral neuropathy drug.