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Identification
NamePralnacasan
Accession NumberDB04875
TypeSmall Molecule
GroupsInvestigational
DescriptionPralnacasan is an orally bioavailable pro-drug of a potent, non-peptide inhibitor of interleukin-1beta converting enzyme (ICE).
Structure
Thumb
Synonyms
HMR 3480
External Identifiers
  • VX-740
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
SaltsNot Available
CategoriesNot Available
UNIIN986NI319S
CAS number192755-52-5
WeightAverage: 523.5378
Monoisotopic: 523.206698307
Chemical FormulaC26H29N5O7
InChI KeyInChIKey=CXAGHAZMQSCAKJ-WAHHBDPQSA-N
InChI
InChI=1S/C26H29N5O7/c1-2-37-26-18(14-21(33)38-26)29-23(34)19-8-5-13-30-20(32)10-9-17(25(36)31(19)30)28-24(35)22-16-7-4-3-6-15(16)11-12-27-22/h3-4,6-7,11-12,17-19,26H,2,5,8-10,13-14H2,1H3,(H,28,35)(H,29,34)/t17-,18-,19-,26+/m0/s1
IUPAC Name
N-[(4S,7S)-4-{[(2R,3S)-2-ethoxy-5-oxooxolan-3-yl]carbamoyl}-6,10-dioxo-octahydro-1H-pyridazino[1,2-a][1,2]diazepin-7-yl]isoquinoline-1-carboxamide
SMILES
CCO[C@@H]1OC(=O)C[C@@H]1NC(=O)[C@@H]1CCCN2N1C(=O)[[email protected]](CCC2=O)NC(=O)C1=NC=CC2=CC=CC=C12
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as n-acyl-alpha amino acids and derivatives. These are compounds containing an alpha amino acid (or a derivative thereof) which bears an acyl group at its terminal nitrogen atom.
KingdomOrganic compounds
Super ClassOrganic acids and derivatives
ClassCarboxylic acids and derivatives
Sub ClassAmino acids, peptides, and analogues
Direct ParentN-acyl-alpha amino acids and derivatives
Alternative Parents
Substituents
  • N-acyl-alpha amino acid or derivatives
  • Alpha-amino acid amide
  • Isoquinoline
  • Pyridine carboxylic acid or derivatives
  • Diazepane
  • 1,2-diazepane
  • Benzenoid
  • Pyridine
  • Pyridazine
  • Gamma butyrolactone
  • 1,2-diazinane
  • Saccharide
  • Heteroaromatic compound
  • Oxolane
  • Secondary carboxylic acid amide
  • Lactone
  • Carboxylic acid hydrazide
  • Carboxylic acid ester
  • Carboxamide group
  • Oxacycle
  • Azacycle
  • Organoheterocyclic compound
  • Monocarboxylic acid or derivatives
  • Carboxylic acid amide
  • Acetal
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Carbonyl group
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationFor the treatment of rheumatoid arthritis (RA).
PharmacodynamicsPralnacasan is a potent, non-peptide inhibitor of interleukin-1beta converting enzyme (ICE). Pralnacasan is an oral, anti-cytokine drug candidate licensed for development by Aventis Pharma from Vertex Pharmaceuticals. In November 2003, Aventis and Vertex Pharmaceuticals announced that they had voluntarily suspended the phase II clinical trials of pralnacasan due to results from an animal toxicity study that demonstrated liver abnormalities after a nine-month exposure to pralnacasan at high doses. While no similar liver toxicity has been seen to date in human trials, the companies will evaluate the animal toxicity results before proceeding with the phase II clinical program.
Mechanism of actionPralnacasan inhibits interleukin-1beta converting enzyme (ICE), an enzyme that regulates the production of IL-1 and IFN gamma - intercellular mediators that initiate and sustain the process of inflammation. Inhibiting ICE may be an effective strategy for curtailing damaging inflammatory processes common to a number of acute and chronic conditions, such as rheumatoid arthritis (RA) and osteoarthritis.
Related Articles
AbsorptionOrally bioavailable
Volume of distributionNot Available
Protein bindingNot Available
MetabolismNot Available
Route of eliminationNot Available
Half lifeNot Available
ClearanceNot Available
ToxicityNot Available
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9821
Blood Brain Barrier-0.8386
Caco-2 permeable-0.7237
P-glycoprotein substrateSubstrate0.7204
P-glycoprotein inhibitor IInhibitor0.7443
P-glycoprotein inhibitor IINon-inhibitor0.9365
Renal organic cation transporterNon-inhibitor0.7706
CYP450 2C9 substrateNon-substrate0.834
CYP450 2D6 substrateNon-substrate0.835
CYP450 3A4 substrateSubstrate0.6186
CYP450 1A2 substrateNon-inhibitor0.8814
CYP450 2C9 inhibitorNon-inhibitor0.7453
CYP450 2D6 inhibitorNon-inhibitor0.8095
CYP450 2C19 inhibitorNon-inhibitor0.7977
CYP450 3A4 inhibitorNon-inhibitor0.5643
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.5861
Ames testNon AMES toxic0.5288
CarcinogenicityNon-carcinogens0.8882
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.4106 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9197
hERG inhibition (predictor II)Non-inhibitor0.5157
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.387 mg/mLALOGPS
logP0.16ALOGPS
logP0.07ChemAxon
logS-3.1ALOGPS
pKa (Strongest Acidic)12.26ChemAxon
pKa (Strongest Basic)1.49ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area147.24 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity131.03 m3·mol-1ChemAxon
Polarizability52.27 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis ReferenceNot Available
General References
  1. Ross J, Brough D, Gibson RM, Loddick SA, Rothwell NJ: A selective, non-peptide caspase-1 inhibitor, VRT-018858, markedly reduces brain damage induced by transient ischemia in the rat. Neuropharmacology. 2007 Oct;53(5):638-42. Epub 2007 Aug 10. [PubMed:17845807 ]
  2. Loher F, Bauer C, Landauer N, Schmall K, Siegmund B, Lehr HA, Dauer M, Schoenharting M, Endres S, Eigler A: The interleukin-1 beta-converting enzyme inhibitor pralnacasan reduces dextran sulfate sodium-induced murine colitis and T helper 1 T-cell activation. J Pharmacol Exp Ther. 2004 Feb;308(2):583-90. Epub 2003 Nov 10. [PubMed:14610233 ]
  3. Rudolphi K, Gerwin N, Verzijl N, van der Kraan P, van den Berg W: Pralnacasan, an inhibitor of interleukin-1beta converting enzyme, reduces joint damage in two murine models of osteoarthritis. Osteoarthritis Cartilage. 2003 Oct;11(10):738-46. [PubMed:13129693 ]
External Links
ATC CodesNot Available
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
unknown
General Function:
Endopeptidase activity
Specific Function:
Thiol protease that cleaves IL-1 beta between an Asp and an Ala, releasing the mature cytokine which is involved in a variety of inflammatory processes. Important for defense against pathogens. Cleaves and activates sterol regulatory element binding proteins (SREBPs). Can also promote apoptosis.
Gene Name:
CASP1
Uniprot ID:
P29466
Molecular Weight:
45158.215 Da
References
  1. Ross J, Brough D, Gibson RM, Loddick SA, Rothwell NJ: A selective, non-peptide caspase-1 inhibitor, VRT-018858, markedly reduces brain damage induced by transient ischemia in the rat. Neuropharmacology. 2007 Oct;53(5):638-42. Epub 2007 Aug 10. [PubMed:17845807 ]
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Drug created on October 20, 2007 05:27 / Updated on August 17, 2016 12:24