Belnacasan (VX765)

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    WARNING: This product is for research use only, not for human or veterinary use.

Description: Belnacasan, also known as VX-765, is designed to inhibit Caspase, which is an enzyme that controls the generation of two cytokines, IL-1b and IL-18. VX-765 has been shown to inhibit acute seizures in preclinical models. In addition, VX-765 has shown activity in preclinical models of chronic epilepsy. VX-765 had been dosed in over 100 patients in phase-I and phase-IIa clinical trials relating to other diseases, including a 28-day phase-IIa clinical trial in patients with psoriasis. It has completed the treatment phase of a phase-IIa clinical trial of VX-765 that enrolled approximately 75 patients with treatment-resistant epilepsy. The double-blind, randomized, placebo-controlled clinical trial was designed to evaluate the safety, tolerability and clinical activity of VX-765.

Price and Availability

Belnacasan (VX-765), purity > 98%, is in stock. The same day shipping out after order is received. Note: the estimated shipping out time for order > 5g may be 2 weeks.

Synonym: VX 765, VX765, VX-765, Belnacasan

IUPAC/Chemical Name: (S)-1-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanoyl)-N-((2R,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)pyrrolidine-2-carboxamide

InChi Key: SJDDOCKBXFJEJB-MOKWFATOSA-N

InChi Code: InChI=1S/C24H33ClN4O6/c1-5-34-23-16(12-18(30)35-23)27-21(32)17-7-6-10-29(17)22(33)19(24(2,3)4)28-20(31)13-8-9-15(26)14(25)11-13/h8-9,11,16-17,19,23H,5-7,10,12,26H2,1-4H3,(H,27,32)(H,28,31)/t16-,17-,19+,23+/m0/s1

SMILES Code: O=C([C@H]1N(C([C@@H](NC(C2=CC=C(N)C(Cl)=C2)=O)C(C)(C)C)=O)CCC1)N[C@@H](C3)[C@H](OCC)OC3=O

Technical Data

Additional Information

VX-765 is a novel Caspase-1 inhibitor being investigated for the treatment of epilepsy., currently  being developed by Vertex.  VX-765 is an orally-absorbed pro-drug of VRT-043198, a potent and selective inhibitor of ICE/caspase-1 sub-family caspases. VRT-043198 exhibits 100-10,000-fold selectivity against other caspase-3 and -6-9.  In cultures of peripheral blood mononuclear cells and whole blood from healthy subjects stimulated with bacterial products, VRT-043198 inhibited the release of Interleukin (IL)-1beta and IL-18, but had little effect on the release of several other cytokines, including IL-1alpha, tumor necrosis factor-alpha, IL-6 and IL-8. In contrast, VRT-043198 had little or no demonstrable activity in cellular models of apoptosis and did not affect the proliferation of activated primary T-cells or T-cell lines. VX-765 was efficiently converted to VRT-043198 when administered orally to mice and inhibited LPS-induced cytokine secretion. In addition, VX-765 reduced disease severity and the expression of inflammatory mediators in models of rheumatoid arthritis and skin inflammation. 
   
According to Vertex's website, VX-765 has been shown to inhibit acute seizures in preclinical models of acute epilepsy and has shown activity in preclinical models of chronic epilepsy that do not respond to standard anti-epileptic drugs. Vertex recently initiated a Phase 2 proof-of-concept clinical trial of VX-765 in patients with epilepsy, which could result in interim clinical data being available as early as the second half of 2010. The Phase 2 trial for VX-765 is expected to enroll approximately 75 patients with treatment-resistant epilepsy.
 
 
 

References

 1: Noe FM, Polascheck N, Frigerio F, Bankstahl M, Ravizza T, Marchini S, Beltrame L, Banderó CR, Löscher W, Vezzani A. Pharmacological blockade of IL-1β/IL-1 receptor type 1 axis during epileptogenesis provides neuroprotection in two rat models of temporal lobe epilepsy. Neurobiol Dis. 2013 Nov;59:183-93. doi: 10.1016/j.nbd.2013.07.015. Epub 2013 Aug 9. PubMed PMID: 23938763.

2: Bialer M, Johannessen SI, Levy RH, Perucca E, Tomson T, White HS. Progress report on new antiepileptic drugs: a summary of the Eleventh Eilat Conference (EILAT XI). Epilepsy Res. 2013 Jan;103(1):2-30. doi: 10.1016/j.eplepsyres.2012.10.001. Epub 2012 Dec 4. Review. PubMed PMID: 23219031.

3: Boxer MB, Shen M, Auld DS, Wells JA, Thomas CJ. A small molecule inhibitor of Caspase 1. 2010 Feb 25 [updated 2011 Mar 3]. Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-. Available from http://www.ncbi.nlm.nih.gov/books/NBK56241/ PubMed PMID: 21735610.

4: Akin D, Ravizza T, Maroso M, Carcak N, Eryigit T, Vanzulli I, Aker RG, Vezzani A, Onat FY. IL-1β is induced in reactive astrocytes in the somatosensory cortex of rats with genetic absence epilepsy at the onset of spike-and-wave discharges, and contributes to their occurrence. Neurobiol Dis. 2011 Dec;44(3):259-69. doi: 10.1016/j.nbd.2011.05.015. Epub 2011 May 30. PubMed PMID: 21645619.

5: Maroso M, Balosso S, Ravizza T, Iori V, Wright CI, French J, Vezzani A. Interleukin-1β biosynthesis inhibition reduces acute seizures and drug resistant chronic epileptic activity in mice. Neurotherapeutics. 2011 Apr;8(2):304-15. doi: 10.1007/s13311-011-0039-z. PubMed PMID: 21431948; PubMed Central PMCID: PMC3101825.

6: Yu JR, Leslie KS. Cryopyrin-associated periodic syndrome: an update on diagnosis and treatment response. Curr Allergy Asthma Rep. 2011 Feb;11(1):12-20. doi: 10.1007/s11882-010-0160-9. PubMed PMID: 21104172; PubMed Central PMCID: PMC3020304.

7: Boxer MB, Quinn AM, Shen M, Jadhav A, Leister W, Simeonov A, Auld DS, Thomas CJ. A highly potent and selective caspase 1 inhibitor that utilizes a key 3-cyanopropanoic acid moiety. ChemMedChem. 2010 May 3;5(5):730-8. doi: 10.1002/cmdc.200900531. PubMed PMID: 20229566; PubMed Central PMCID: PMC3062473.

8: Ravizza T, Noé F, Zardoni D, Vaghi V, Sifringer M, Vezzani A. Interleukin Converting Enzyme inhibition impairs kindling epileptogenesis in rats by blocking astrocytic IL-1beta production. Neurobiol Dis. 2008 Sep;31(3):327-33. doi: 10.1016/j.nbd.2008.05.007. Epub 2008 May 29. PubMed PMID: 18632279.

9: 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 PMID: 18081302.

10: Cornelis S, Kersse K, Festjens N, Lamkanfi M, Vandenabeele P. Inflammatory caspases: targets for novel therapies. Curr Pharm Des. 2007;13(4):367-85. Review. PubMed PMID: 17311555