Zenarestat (FK-366, FR-74366) is a highly potent, reversible, and mixed type inhibitor of aldose reductase (AR) with IC50 of 3.6 and 4.4 nM for purified AR from the rat sciatic nerve and rat lens.
Zenarestat (FK-366, FR-74366) inhibited sorbitol accumulation in the isolated human erythrocyte (IC50 = 1.6 mumol/L), rat lens (IC50 = 39 mumol/L), and rat sciatic nerve (IC50 = 17 mumol/L) incubated with high glucose concentrations.
Oral administration of FR74366 to streptozotocin (STZ)-induced diabetic rats for 2 weeks decreased sorbitol levels (ED50 = 3.7 mg/kg for sciatic nerve, 23 mg/kg for lens, 52 mg/kg for retina, and 62 mg/kg for renal cortex).
Zenarestat (FK-366, FR-74366) induced recovery of reduced motor nerve conduction velocity in diabetic rats, correlated well with reduction of accumulated sorbitol and fructose levels and normalization of decreased myoinositol levels.