VRT-043198   Click here for help

GtoPdb Ligand ID: 9034

PDB Ligand Immunopharmacology Ligand
Compound class: Synthetic organic
Comment: VRT-043198 generated from the prodrug belnacasan (VX-765) is a potent and selective inhibitor of caspase-1 from Vertex. When administered orally to mice, it inhibits lipopolysaccharide-induced cytokine secretion and reduces disease severity and the expression of inflammatory mediators in models of rheumatoid arthritis and skin inflammation, suggesting that as a cytokine inhibitor it could be useful for treatment of inflammatory diseases [1].
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 10
Hydrogen bond donors 4
Rotatable bonds 12
Topological polar surface area 158.9
Molecular weight 480.18
XLogP 1.34
No. Lipinski's rules broken 0
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Canonical SMILES O=CC(NC(=O)C1CCCN1C(=O)C(C(C)(C)C)NC(=O)c1ccc(c(c1)Cl)N)CC(=O)O
Isomeric SMILES O=C[C@@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](C(C)(C)C)NC(=O)c1ccc(c(c1)Cl)N)CC(=O)O
InChI InChI=1S/C22H29ClN4O6/c1-22(2,3)18(26-19(31)12-6-7-15(24)14(23)9-12)21(33)27-8-4-5-16(27)20(32)25-13(11-28)10-17(29)30/h6-7,9,11,13,16,18H,4-5,8,10,24H2,1-3H3,(H,25,32)(H,26,31)(H,29,30)/t13-,16-,18+/m0/s1
Bioactivity Comments
Inhibits caspase-1 (Ki = 0.8 nM) and caspase-4 (Ki < 0.6 nM) and shows 100- to 10,000-fold selectivity against caspases -3 and -6 to -9. Inhibits the release of interleukin (IL)-1β and IL-18, but has little effect on the release of several other cytokines, including IL-1α, tumor necrosis factor-α, IL-6 and IL-8 [1].
Selectivity at enzymes
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
Caspase 4 Hs Inhibitor Inhibition 9.4 pKi - 1
pKi 9.4 (Ki 4x10-10 M) [1]
Caspase 1 Primary target of this compound Hs Inhibitor Inhibition 9.1 pKi - 1
pKi 9.1 (Ki 8x10-10 M) Derived from pro-drug belnacasan [1]