(S)-1-((S)-2-{[1-(4-amino-3-chloro-phenyl)-methanoyl]-amino}-3,3-dimethyl-butanoyl)-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.
From: Department of Chemistry, Drug Discovery Support Unit, Vertex Pharmaceuticals, Inc., 130 Waverly St., Cambridge, MA 02139, USA.
The Journal of pharmacology and experimental therapeutics
- Publish Date: May 2007
- ISSN: 0022-3565
- Volume: 321
- Issue: 2
- Pages: 509-16
- Medium: Print
- Language: English
- Citation (JAMA): Wannamaker Woods, Davies Robert, Namchuk Mark, et al. (S)-1-((S)-2-{[1-(4-amino-3-chloro-phenyl)-methanoyl]-amino}-3,3-dimethyl-butanoyl)-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. May 2007;321:509-16
Abstract
(S)-1-((S)-2-{[1-(4-amino-3-chloro-phenyl)-methanoyl]-amino}-3,3-dimethyl-butanoyl)-pyrrolidine-2-carboxylic acid ((2R,3S)-2-ethoxy-5-oxo-tetrahydro-furan-3-yl)-amide (VX-765) is an orally absorbed prodrug of (S)-3-({1-[(S)-1-((S)-2-{[1-(4-amino-3-chlorophenyl)-methanoyl]-amino}-3,3-dimethyl-butanoyl)-pyrrolidin-2yl]-methanoyl}-amino)-4-oxo-butyric acid (VRT-043198), a potent and selective inhibitor of interleukin-converting enzyme/caspase-1 subfamily caspases. VRT-043198 exhibits 100- to 10,000-fold selectivity against other caspase-3 and -6 to -9. The therapeutic potential of VX-765 was assessed by determining the effects of VRT-043198 on cytokine release by monocytes in vitro and of orally administered VX-765 in several animal models in vivo. 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 it 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 it 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 it inhibited lipopolysaccharide-induced cytokine secretion. In addition, VX-765 reduced disease severity and the expression of inflammatory mediators in models of rheumatoid arthritis and skin inflammation. These data suggest that VX-765 is a novel cytokine inhibitor useful for treatment of inflammatory diseases.
Mesh Headings (Keywords): 4-Aminobenzoic Acid, Administration, Oral, Animals, Anti-Inflammatory Agents, Non-Steroidal, Apoptosis, Arthritis, Experimental, Caspase 1, Dipeptides, Humans, Hypersensitivity, Delayed, Interleukin-18, Interleukin-1beta, Lipopolysaccharides, Male, Mice, Mice, Inbred DBA, Oxazolone, Protease Inhibitors
Check for Full Text / PubMed Unique Identifier (PMID): 17289835
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