Pralnacasan

Identification

Name
Pralnacasan
Accession Number
DB04875
Type
Small Molecule
Groups
Investigational
Description

Pralnacasan is an orally bioavailable pro-drug of a potent, non-peptide inhibitor of interleukin-1beta converting enzyme (ICE).

Structure
Thumb
Synonyms
  • HMR 3480
External IDs
VX-740
Categories
Not Available
UNII
N986NI319S
CAS number
192755-52-5
Weight
Average: 523.5378
Monoisotopic: 523.206698307
Chemical Formula
C26H29N5O7
InChI Key
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[[email protected]@H]1OC(=O)C[[email protected]@H]1NC(=O)[[email protected]@H]1CCCN2N1C(=O)[[email protected]](CCC2=O)NC(=O)C1=NC=CC2=CC=CC=C12

Pharmacology

Indication

For the treatment of rheumatoid arthritis (RA).

Structured Indications
Not Available
Pharmacodynamics

Pralnacasan 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 action

Pralnacasan 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.

TargetActionsOrganism
UCaspase-1Not AvailableHuman
Absorption

Orally bioavailable

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
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

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
PubChem Compound
153270
PubChem Substance
175426882
ChemSpider
135089
BindingDB
50189360
ChEMBL
CHEMBL437526

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 Solubility0.387 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 FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
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)

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 dipeptides. These are organic compounds containing a sequence of exactly two alpha-amino acids joined by a peptide bond.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
Dipeptides
Alternative Parents
N-acyl-alpha amino acids and derivatives / Alpha amino acid amides / Isoquinolines and derivatives / Pyridinecarboxylic acids and derivatives / 2-heteroaryl carboxamides / 1,2-diazepanes / Benzenoids / Diacylhydrazines / Diazinanes / Gamma butyrolactones
show 14 more
Substituents
Alpha-dipeptide / N-acyl-alpha amino acid or derivatives / Alpha-amino acid amide / Alpha-amino acid or derivatives / Isoquinoline / Pyridine carboxylic acid or derivatives / 2-heteroaryl carboxamide / 1,2-diazepane / Diazepane / Diacylhydrazine
show 26 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Details
1. Caspase-1
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. Cle...
Gene Name
CASP1
Uniprot ID
P29466
Uniprot Name
Caspase-1
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]

Drug created on October 20, 2007 05:27 / Updated on December 01, 2017 15:33