Zenarestat

Identification

Name
Zenarestat
Accession Number
DB02132  (EXPT03287, DB06424)
Type
Small Molecule
Groups
Experimental
Description
Not Available
Structure
Thumb
Synonyms
Not Available
Categories
Not Available
UNII
180C9PJ8JT
CAS number
112733-06-9
Weight
Average: 441.636
Monoisotopic: 439.957475409
Chemical Formula
C17H11BrClFN2O4
InChI Key
SXONDGSPUVNZLO-UHFFFAOYSA-N
InChI
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)
IUPAC Name
2-{3-[(4-bromo-2-fluorophenyl)methyl]-7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-1-yl}acetic acid
SMILES
OC(=O)CN1C(=O)N(CC2=C(F)C=C(Br)C=C2)C(=O)C2=C1C=C(Cl)C=C2

Pharmacology

Indication

Investigated for use/treatment in neuropathy (diabetic).

Structured Indications
Not Available
Pharmacodynamics
Not Available
Mechanism of action

Polyneuropathy, damage of peripheral neurons, is common in diabetes mellitus patients and causes pain, sensory and motor deficits in the limbs. Zenarestat is an aldose reductase inhibitor which inhibits the metabolism of glucose by the polyol pathway, which possibly slows or reduces progression of polyneuropathy. Chronic hyperglycemia affects peripheral nerves by an extracellular mechanism with many types of glycation reactions and chemical rearrangements, and an intracellular route involving increased amounts of glucose passing through the polyol pathway. The polyol pathway allows cells to produce fructose from glucose, and has two steps, which require energy and enzymes. Aldose reductase catalyzes the conversion of glucose to sorbitol in the first step, while the second involves the oxidation of nicotinamide adenine dicnucleotide phosphate (conversion of NADPH to NADP). Chronic hyperglycemia causes damage by overactivity of the polyol pathway, causing a decrease in cellular NADPH levels, reducing the amount of glutathione (a free radical scavenger), and nitric oxide (a vasodilator), as well as increasing cellular sorbital levels, causing decreased levels of myo-inositol (necessary for Na-K ATPase function) and increased fructose, thus increasing AGE (advanced glycosylation end products), the byproduct of the polyol pathway. The suppression of the first step in the polyol pathway by zenarestat prevents these deleterious processes from occuring.

TargetActionsOrganism
UAldose reductaseNot AvailableHuman
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity
Not Available
Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

General References
  1. Chalk C, Benstead TJ, Moore F: Aldose reductase inhibitors for the treatment of diabetic polyneuropathy. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD004572. [PubMed:17943821]
External Links
PubChem Compound
5724
PubChem Substance
46507491
ChemSpider
5522
BindingDB
16496
ChEMBL
CHEMBL10413
HET
ZES
Wikipedia
Zenarestat
PDB Entries
1iei

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0101 mg/mLALOGPS
logP3.26ALOGPS
logP3.55ChemAxon
logS-4.6ALOGPS
pKa (Strongest Acidic)3.41ChemAxon
pKa (Strongest Basic)-7.4ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area77.92 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity95.13 m3·mol-1ChemAxon
Polarizability36.5 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9661
Blood Brain Barrier+0.7479
Caco-2 permeable-0.5579
P-glycoprotein substrateNon-substrate0.657
P-glycoprotein inhibitor INon-inhibitor0.8388
P-glycoprotein inhibitor IINon-inhibitor0.8866
Renal organic cation transporterNon-inhibitor0.8342
CYP450 2C9 substrateNon-substrate0.7536
CYP450 2D6 substrateNon-substrate0.8291
CYP450 3A4 substrateNon-substrate0.5775
CYP450 1A2 substrateNon-inhibitor0.5
CYP450 2C9 inhibitorNon-inhibitor0.7337
CYP450 2D6 inhibitorNon-inhibitor0.9414
CYP450 2C19 inhibitorNon-inhibitor0.712
CYP450 3A4 inhibitorNon-inhibitor0.6862
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.6255
Ames testNon AMES toxic0.7627
CarcinogenicityNon-carcinogens0.8469
BiodegradationNot ready biodegradable0.9956
Rat acute toxicity2.0485 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8802
hERG inhibition (predictor II)Non-inhibitor0.8317
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as quinazolines. These are compounds containing a quinazoline moiety, which is made up of two fused six-member aromatic rings, a benzene ring and a pyrimidine ring.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Diazanaphthalenes
Sub Class
Benzodiazines
Direct Parent
Quinazolines
Alternative Parents
Alpha amino acids and derivatives / Pyrimidones / Bromobenzenes / Fluorobenzenes / Aryl bromides / Aryl chlorides / Aryl fluorides / Vinylogous amides / Heteroaromatic compounds / Ureas
show 12 more
Substituents
Alpha-amino acid or derivatives / Quinazoline / Halobenzene / Fluorobenzene / Bromobenzene / Pyrimidone / Aryl bromide / Aryl chloride / Aryl fluoride / Aryl halide
show 24 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Details
1. Aldose reductase
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Glyceraldehyde oxidoreductase activity
Specific Function
Catalyzes the NADPH-dependent reduction of a wide variety of carbonyl-containing compounds to their corresponding alcohols with a broad range of catalytic efficiencies.
Gene Name
AKR1B1
Uniprot ID
P15121
Uniprot Name
Aldose reductase
Molecular Weight
35853.125 Da

Drug created on June 13, 2005 07:24 / Updated on December 01, 2017 14:53