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(S)-1-((S)-2-{[1-(4-Amino-3-chloro-phenyl)-methanoyl]-amino}-3,3-dimethyl-butanoyl)-pyrrolidine-2-carboxylic acid ((2 R,3 S)-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-1β and IL-18

Wannamaker, Woods, Davies, Robert, Namchuk, Mark, Pollard, John, Ford, Pamella, Ku, George, Decker, Caroline, Charifson, Paul, Weber, Peter, Germann, Ursula A., Kuida, Keisuke, Randle, John C.R.·2007·The Journal of Pharmacology and Experimental Therapeutics
DOI 10.1124/jpet.106.111344
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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…

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Metadata

Authors
Wannamaker, W., Davies, R., Namchuk, M., Pollard, J., Ford, P., Ku, G., Decker, C., Charifson, P., Weber, P., Germann, U. A., Kuida, K., & Randle, J. C. R.
Venue
The Journal of Pharmacology and Experimental Therapeutics
Publisher
Elsevier BV
Published
2007-05
Volume
321
Issue
2
Pages
509-516
ISSN
0022-3565
DOI
10.1124/jpet.106.111344
Cited by
315
References
0
Language
en
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