(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.

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.

• Authors: Woods Wannamaker, Robert Davies, Mark Namchuk, John Pollard, Pamella Ford, George Ku, Caroline Decker, Paul Charifson, Peter Weber, Ursula A Germann, Keisuke Kuida, John C R Randle
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 321 Issue 2 Pg. 509-16 (May 2007) ISSN: 0022-3565 [Print] United States
• PMID: 17289835 (Publication Type: Journal Article)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Caspase Inhibitors
• Dipeptides
• Interleukin-18
• Interleukin-1beta
• Lipopolysaccharides
• Protease Inhibitors
• para-Aminobenzoates
• belnacasan
• Oxazolone
• 4-Aminobenzoic Acid

Topics

• 4-Aminobenzoic Acid (pharmacology)
• Administration, Oral
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Apoptosis (drug effects)
• Arthritis, Experimental (drug therapy)
• Caspase Inhibitors
• Dipeptides (pharmacology)
• Humans
• Hypersensitivity, Delayed (drug therapy)
• Interleukin-18 (metabolism)
• Interleukin-1beta (metabolism)
• Lipopolysaccharides (pharmacology)
• Male
• Mice
• Mice, Inbred DBA
• Oxazolone (toxicity)
• Protease Inhibitors (pharmacology)
• para-Aminobenzoates