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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on February 8, 2007; DOI: 10.1124/jpet.106.111344

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Received for publication July 31, 2006.
Revised January 9, 2007.
Accepted for publication February 5, 2007.

VX-765, an orally available selective interleukin converting enzyme (ICE)/caspase-1 inhibitor exhibits potent anti-inflammatory activities by inhibiting the release of IL-1b and IL-18

Woods Wannamaker 1, Robert Davies 1, Mark Namchuk 1, John Pollard 1, Pamella Ford 1, George Ku 1, Caroline Decker 1, Paul Charifson 1, Peter Weber 1, Ursula A Germann 1, Keisuke Kuida 1, John Randle 1*

1 Vertex Pharmaceuticals

* Address correspondence to: E-mail: john_randle{at}vrtx.com

Abstract

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. 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)-1{beta} and IL-18, but had little effect on the release of several other cytokines, including IL-1{alpha}, 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. These data suggest that VX-765 is a novel cytokine inhibitor useful for treatment of inflammatory diseases.


Key words: arthritis, caspase, cytokine, inflammation, prodrug, protease inhibitor


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