Accession NumberDB05507
TypeSmall Molecule

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.

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Approved Over the Counter ProductsNot Available
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Investigated for use/treatment in inflammatory disorders (unspecified) and psoriasis and psoriatic disorders.

Structured Indications Not Available

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.

TargetKindPharmacological actionActionsOrganismUniProt ID
Caspase-1ProteinunknownNot AvailableHumanP29466 details
Interleukin-1 betaProteinunknownNot AvailableHumanP01584 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
Drug Interactions Not Available
Food InteractionsNot Available
Synthesis ReferenceNot Available
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. [PubMed:18081302 ]
  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. [PubMed:17311555 ]
  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. [PubMed:17289835 ]
  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. [PubMed:16886979 ]
  5. Linton SD: Caspase inhibitors: a pharmaceutical industry perspective. Curr Top Med Chem. 2005;5(16):1697-717. [PubMed:16375749 ]
  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. [PubMed:16081838 ]
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FDA labelNot Available
MSDSNot Available
Clinical Trials
Clinical Trials
2CompletedTreatmentEpilepsy, Localization Related1
ManufacturersNot Available
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Dosage formsNot Available
PricesNot Available
PatentsNot Available
Experimental PropertiesNot Available
Predicted PropertiesNot Available
Predicted ADMET featuresNot Available
Mass Spec (NIST)Not Available
Spectrum TypeDescriptionSplash Key
ClassificationNot classified


Pharmacological action
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:
Uniprot ID:
Molecular Weight:
45158.215 Da
Pharmacological action
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, B-cell activation and antibody production, and fibroblast proliferation and collagen production. Promotes Th17 differentiation of T-cells.
Gene Name:
Uniprot ID:
Molecular Weight:
30747.7 Da
Drug created on November 18, 2007 11:25 / Updated on August 17, 2016 12:24