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Details

Stereochemistry ACHIRAL
Molecular Formula C17H11BrClFN2O4
Molecular Weight 441.636
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of ZENARESTAT

SMILES

OC(=O)CN1C(=O)N(CC2=C(F)C=C(Br)C=C2)C(=O)C3=C1C=C(Cl)C=C3

InChI

InChIKey=SXONDGSPUVNZLO-UHFFFAOYSA-N
InChI=1S/C17H11BrClFN2O4/c18-10-2-1-9(13(20)5-10)7-22-16(25)12-4-3-11(19)6-14(12)21(17(22)26)8-15(23)24/h1-6H,7-8H2,(H,23,24)

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Description

Zenarestat (FK-366; FR-74366) is an aldose reductase (AR) inhibitor investigated as a treatment for diabetic neuropathy and cataract. Zenarestat is a highly specific AR inhibitor, it did not affect the activities of enzymes in the glycolysis pathway, the pentose-phosphate pathway and NADPH-dependent enzymes such as NOS and glutathione reductase. Zenarestat exhibited some inhibition of aldehyde reductase, the most closely related enzyme to AR, however, its IC50 was evidently higher than that for AR. Zenarestat dose-dependently reduced the elevated sorbitol concentration in the lens, retina sciatic nerve, and renal cortex. The most potent effect of zenarestat was seen in the sciatic nerve. Zenarestat inhibits cataract formation and to counteract reduced motor nerve conduction velocity in the streptozotocin-induced diabetic rat. Zenarestat had been in clinical trials for the treatment of diabetic neuropathy however future development was discontinued due to dose-dependent renal toxicity.

Originator

Approval Year

Targets

Primary TargetPharmacologyConditionPotency
8.0 nM [IC50]

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Unknown

PubMed

Patents

Sample Use Guides

In Vivo Use Guide
150, 300, or 600 mg twice daily for 52 weeks
Route of Administration: Oral
In Vitro Use Guide
Aldose Reductase (AR) activity was assayed spectrophotometrically using an Ultrolab system 2068 reaction rate analyzer (LKB. Bromma, Sweden). For this assay, the oxidation of NADPH to NADP was measured at 340 nm and 37°C for 2 minutes after starting the reaction by addition of glyceraldehyde as the substrate. One unit of enzyme activity was defined as the amount of enzyme that caused oxidation of 1 nmol NADPH per minute. Inhibitors (Zenarestat) were dissolved in dimethyl sulfoxide (DMSO) to make 1-mmol/L solutions and diluted with distilled water. The reaction mixtures contained 50 mmol/L sodium phosphate buffer (pH 6.2), 400 mmol/L lithium sulfate, 3 mmol/L glyceraldehyde, 0.125 mmol/L NADPH, 4 to 8 U of enzyme, and various concentrations of inhibitor in a total volume of 1.00 mL. The final concentration of DMSO in the reaction mixture never exceeded l%, a concentration that did not influence AR activity.