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
SMILES
OC(=O)CN1C(=O)N(CC2=CC=C(Br)C=C2F)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)
| Molecular Formula | C17H11BrClFN2O4 |
| Molecular Weight | 441.636 |
| Charge | 0 |
| Count |
|
| Stereochemistry | ACHIRAL |
| Additional Stereochemistry | No |
| Defined Stereocenters | 0 / 0 |
| E/Z Centers | 0 |
| Optical Activity | NONE |
DescriptionCurator's Comment: The description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/pubmed/10449124 | https://www.ncbi.nlm.nih.gov/pubmed/1898618 | https://www.ncbi.nlm.nih.gov/pubmed/15857120
Curator's Comment: The description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/pubmed/10449124 | https://www.ncbi.nlm.nih.gov/pubmed/1898618 | https://www.ncbi.nlm.nih.gov/pubmed/15857120
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
Cmax
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
22.6 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8300896/ |
150 mg single, oral dose: 150 mg route of administration: Oral experiment type: SINGLE co-administered: |
ZENARESTAT plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
|
39 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8300896/ |
300 mg single, oral dose: 300 mg route of administration: Oral experiment type: SINGLE co-administered: |
ZENARESTAT plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
|
75.7 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8300896/ |
600 mg single, oral dose: 600 mg route of administration: Oral experiment type: SINGLE co-administered: |
ZENARESTAT plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
|
41.6 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8300896/ |
600 mg single, oral dose: 600 mg route of administration: Oral experiment type: SINGLE co-administered: |
ZENARESTAT plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED |
|
15.1 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8300896/ |
300 mg 2 times / day multiple, oral dose: 300 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
ZENARESTAT plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED |
|
17.6 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8300896/ |
300 mg 2 times / day multiple, oral dose: 300 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
ZENARESTAT plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED |
AUC
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
66.8 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8300896/ |
150 mg single, oral dose: 150 mg route of administration: Oral experiment type: SINGLE co-administered: |
ZENARESTAT plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
|
135 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8300896/ |
300 mg single, oral dose: 300 mg route of administration: Oral experiment type: SINGLE co-administered: |
ZENARESTAT plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
|
309 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8300896/ |
600 mg single, oral dose: 600 mg route of administration: Oral experiment type: SINGLE co-administered: |
ZENARESTAT plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
|
218 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8300896/ |
600 mg single, oral dose: 600 mg route of administration: Oral experiment type: SINGLE co-administered: |
ZENARESTAT plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED |
|
68.7 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8300896/ |
300 mg 2 times / day multiple, oral dose: 300 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
ZENARESTAT plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED |
|
74.1 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8300896/ |
300 mg 2 times / day multiple, oral dose: 300 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
ZENARESTAT plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED |
T1/2
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
7.7 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8300896/ |
150 mg single, oral dose: 150 mg route of administration: Oral experiment type: SINGLE co-administered: |
ZENARESTAT plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
|
8.8 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8300896/ |
300 mg single, oral dose: 300 mg route of administration: Oral experiment type: SINGLE co-administered: |
ZENARESTAT plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
|
8.2 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8300896/ |
600 mg single, oral dose: 600 mg route of administration: Oral experiment type: SINGLE co-administered: |
ZENARESTAT plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
|
7.7 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8300896/ |
600 mg single, oral dose: 600 mg route of administration: Oral experiment type: SINGLE co-administered: |
ZENARESTAT plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED |
|
10.2 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8300896/ |
300 mg 2 times / day multiple, oral dose: 300 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
ZENARESTAT plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED |
Funbound
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
0.6% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8079505/ |
ZENARESTAT plasma | Homo sapiens |
Doses
| Dose | Population | Adverse events |
|---|---|---|
300 mg 2 times / day steady-state, oral Highest studied dose Dose: 300 mg, 2 times / day Route: oral Route: steady-state Dose: 300 mg, 2 times / day Sources: |
healthy, ADULT Health Status: healthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: |
|
600 mg single, oral Highest studied dose |
healthy, ADULT Health Status: healthy Age Group: ADULT Sex: M+F Food Status: FASTED Sources: |
|
600 mg single, oral Highest studied dose |
healthy, ADULT Health Status: healthy Age Group: ADULT Sex: M+F Food Status: FED Sources: |
Other AEs: dry mouth... |
AEs
| AE | Significance | Dose | Population |
|---|---|---|---|
| dry mouth | 1 pt | 600 mg single, oral Highest studied dose |
healthy, ADULT Health Status: healthy Age Group: ADULT Sex: M+F Food Status: FED Sources: |
PubMed
| Title | Date | PubMed |
|---|---|---|
| Discovery of 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]indole-N-acetic acid (lidorestat) and congeners as highly potent and selective inhibitors of aldose reductase for treatment of chronic diabetic complications. | 2005-05-05 |
|
| Role of aldose reductase and oxidative damage in diabetes and the consequent potential for therapeutic options. | 2005-05 |
Patents
Sample Use Guides
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.
| Substance Class |
Chemical
Created
by
admin
on
Edited
Mon Mar 31 18:11:33 GMT 2025
by
admin
on
Mon Mar 31 18:11:33 GMT 2025
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| Record UNII |
180C9PJ8JT
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| Record Status |
Validated (UNII)
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| Record Version |
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C72880
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112733-06-9
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C72879
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DB02132
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m986
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SUB00145MIG
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Zenarestat
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KK-39
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100000079393
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| Related Record | Type | Details | ||
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TARGET -> INHIBITOR |
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ACTIVE MOIETY |
