Identification
NameZenarestat
Accession NumberDB02132  (EXPT03287, DB06424)
TypeSmall Molecule
GroupsExperimental
DescriptionNot Available
Structure
Thumb
SynonymsNot Available
External IDs Not Available
Product Ingredients Not Available
Approved Prescription ProductsNot Available
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
CategoriesNot Available
UNII180C9PJ8JT
CAS number112733-06-9
WeightAverage: 441.636
Monoisotopic: 439.957475409
Chemical FormulaC17H11BrClFN2O4
InChI KeySXONDGSPUVNZLO-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
PharmacodynamicsNot 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.

TargetKindPharmacological actionActionsOrganismUniProt ID
Aldose reductaseProteinunknownNot AvailableHumanP15121 details
Related Articles
AbsorptionNot Available
Volume of distributionNot Available
Protein bindingNot Available
MetabolismNot Available
Route of eliminationNot Available
Half lifeNot Available
ClearanceNot Available
ToxicityNot Available
Affected organismsNot Available
PathwaysNot Available
Pharmacogenomic Effects/ADRs Not Available
Interactions
Drug Interactions Not Available
Food InteractionsNot Available
References
Synthesis ReferenceNot Available
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
ATC CodesNot Available
AHFS CodesNot Available
PDB Entries
FDA labelNot Available
MSDSNot Available
Clinical Trials
Clinical Trials Not Available
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental PropertiesNot 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
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, NegativeNot Available
Taxonomy
DescriptionThis compound belongs to the class of chemical entities 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.
KingdomChemical entities
Super ClassOrganic compounds
ClassOrganoheterocyclic compounds
Sub ClassDiazanaphthalenes
Direct ParentQuinazolines
Alternative ParentsAlpha amino acids and derivatives / Pyrimidones / Bromobenzenes / Fluorobenzenes / Aryl bromides / Aryl chlorides / Aryl fluorides / Vinylogous amides / Heteroaromatic compounds / Ureas
SubstituentsAlpha-amino acid or derivatives / Quinazoline / Halobenzene / Fluorobenzene / Bromobenzene / Pyrimidone / Aryl bromide / Aryl chloride / Aryl fluoride / Aryl halide
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot Available

Targets

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
Molecular Weight:
35853.125 Da
Drug created on June 13, 2005 07:24 / Updated on July 18, 2017 17:06