<b>Discovery of a novel benzothiadiazine-based selective aldose reductase inhibitor as potential therapy for diabetic </b><b>peripheral</b><b> </b><b>neuropathy</b>

Abstract

<p dir="ltr">Aldose reductase2 (ALR2)<a href="" target="_blank">, 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 (</a>DPN). However, lots of ALR2 inhibitors showed serious side-effects due to poor selectivity over aldehyde reductase (ALR1). Herein, we described the discovery of a series of <a href="" target="_blank">benzothiadiazine acetic acid</a> derivatives as potent and selective inhibitors against ALR2 and evaluation of their anti-DPN activities <i>in vivo</i>. Compound <b>15c </b>carrying carbonyl group at the 3-position of thiadiazine ring showed high potent inhibition against ALR2 (IC<sub>50</sub> = 33.19 nM) and about 16109-fold selectivity for ALR2 over ALR1. <a href="" target="_blank">Cytotoxicity assays ensured the primary biosafety of <b>15c</b>. Further pharmacokinetic assay in rats indicated</a> <b>15c</b> had a good pharmacokinetic feature (T<sub>1/2</sub> = 5.60 h, AUC<sub>(0-t) </sub>= 598.57±216.5 μg/mL*h), which was superior to Epalrestat (T<sub>1/2</sub> = 2.23 h, AUC<sub>(0-t)</sub> = 20.43±3.7 μg/mL*h). Finally, in streptozotocin (STZ)-induced diabetic rat model,<b> 15c</b> 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 <a href="" target="_blank">paw withdrawal mechanical threshold</a> (PWMT). Combined the above investigations, we proposed that <b>15c</b> might represent a promising lead compound for discovery of anti-diabetic peripheral neuropathy drug.</p>