NAV

VX-765

Identification

Generic Name
VX-765
DrugBank Accession Number
DB05507
Background

VX-765 is the orally available prodrug of a potent and selective competitive inhibitor of ICE/caspase-1 (VRT-043198). VX-765 is currently under clinical development for the treatment of inflammatory and autoimmune conditions, as it blocks the hypersensitive response to an inflammatory stimulus.

Type
Small Molecule
Groups
Investigational
Synonyms
Not Available
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Pharmacology

Indication

Investigated for use/treatment in inflammatory disorders (unspecified) and psoriasis and psoriatic disorders.

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Contraindications & Blackbox Warnings
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Pharmacodynamics

VX-765 is an orally-absorbed pro-drug of VRT-043198, a potent and selective inhibitor of ICE/caspase-1 sub-family caspases. It has been shown to reduce disease severity and the expression of inflammatory mediators in models of rheumatoid arthritis and skin inflammation, suggesting that it may be useful for treatment of inflammatory diseases.

Mechanism of action

VX-765 is a potent and selective inhibitor of ICE/caspase-1 sub-family caspases. In preclinical trials, VX-765 was efficiently converted to VRT-043198 when administered orally to mice and inhibited LPS-induced cytokine secretion. The result was a blocking of IL-1beta and IL-18 secretion, with out much effect on the release of several other cytokines, including IL-1{alpha}, tumor necrosis factor-{alpha}, IL-6 and IL-8. There was also no demonstrable activity in cellular models of apoptosis and it did not affect the proliferation of activated primary T-cells or T-cell lines.

TargetActionsOrganism
UCaspase-1Not AvailableHumans
UInterleukin-1 betaNot AvailableHumans
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

Adverse Effects
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Toxicity

Not Available

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Not Available
Food Interactions
Not Available

Categories

Drug Categories
Classification
Not classified
Affected organisms
Not Available

Chemical Identifiers

UNII
00OLE78529
CAS number
Not Available
InChI Key
Not Available
InChI
Not Available
IUPAC Name
Not Available
SMILES
Not Available

References

General References
  1. Tanoury GJ, Chen M, Dong Y, Forslund RE, Magdziak D: Development of a novel Pd-catalyzed N-acyl vinylogous carbamate synthesis for the key intermediate of ICE inhibitor VX-765. Org Lett. 2008 Jan 17;10(2):185-8. Epub 2007 Dec 15. [Article]
  2. Cornelis S, Kersse K, Festjens N, Lamkanfi M, Vandenabeele P: Inflammatory caspases: targets for novel therapies. Curr Pharm Des. 2007;13(4):367-85. [Article]
  3. Wannamaker W, Davies R, Namchuk M, Pollard J, Ford P, Ku G, Decker C, Charifson P, Weber P, Germann UA, Kuida K, Randle JC: (S)-1-((S)-2-{[1-(4-amino-3-chloro-phenyl)-methanoyl]-amino}-3,3-dimethyl-butanoy l)-pyrrolidine-2-carboxylic acid ((2R,3S)-2-ethoxy-5-oxo-tetrahydro-furan-3-yl)-amide (VX-765), an orally available selective interleukin (IL)-converting enzyme/caspase-1 inhibitor, exhibits potent anti-inflammatory activities by inhibiting the release of IL-1beta and IL-18. J Pharmacol Exp Ther. 2007 May;321(2):509-16. Epub 2007 Feb 8. [Article]
  4. Ravizza T, Lucas SM, Balosso S, Bernardino L, Ku G, Noe F, Malva J, Randle JC, Allan S, Vezzani A: Inactivation of caspase-1 in rodent brain: a novel anticonvulsive strategy. Epilepsia. 2006 Jul;47(7):1160-8. [Article]
  5. Linton SD: Caspase inhibitors: a pharmaceutical industry perspective. Curr Top Med Chem. 2005;5(16):1697-717. [Article]
  6. Stack JH, Beaumont K, Larsen PD, Straley KS, Henkel GW, Randle JC, Hoffman HM: IL-converting enzyme/caspase-1 inhibitor VX-765 blocks the hypersensitive response to an inflammatory stimulus in monocytes from familial cold autoinflammatory syndrome patients. J Immunol. 2005 Aug 15;175(4):2630-4. [Article]
PubChem Substance
347910179
Wikipedia
Belnacasan

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedTreatmentPartial Epilepsy1
2CompletedTreatmentPsoriasis1
2TerminatedTreatmentEpilepsy1

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
Not Available
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available
Chromatographic Properties
Collision Cross Sections (CCS)
Not Available

Targets

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Details1. Caspase-1
Kind
Protein
Organism
Humans
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
Details2. Interleukin-1 beta
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Protein domain specific binding
Specific Function
Potent proinflammatory cytokine. Initially discovered as the major endogenous pyrogen, induces prostaglandin synthesis, neutrophil influx and activation, T-cell activation and cytokine production, ...
Gene Name
IL1B
Uniprot ID
P01584
Uniprot Name
Interleukin-1 beta
Molecular Weight
30747.7 Da

Drug created at November 18, 2007 18:25 / Updated at June 12, 2020 16:52