title: (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.affiliation: Department of Chemistry, Drug Discovery Support Unit, Vertex Pharmaceuticals, Inc., 130 Waverly St., Cambridge, MA 02139, USA.
authors.forename: Woods
authors.initials: W
authors.lastname: Wannamaker
authors.forename: Robert
authors.initials: R
authors.lastname: Davies
authors.forename: Mark
authors.initials: M
authors.lastname: Namchuk
authors.forename: John
authors.initials: J
authors.lastname: Pollard
authors.forename: Pamella
authors.initials: P
authors.lastname: Ford
authors.forename: George
authors.initials: G
authors.lastname: Ku
authors.forename: Caroline
authors.initials: C
authors.lastname: Decker
authors.forename: Paul
authors.initials: P
authors.lastname: Charifson
authors.forename: Peter
authors.initials: P
authors.lastname: Weber
authors.forename: Ursula A
authors.initials: UA
authors.lastname: Germann
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kuida
authors.forename: John C R
authors.initials: JC
authors.lastname: Randle
mesh_terms: D010129:4-Aminobenzoic Acid / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001169:Arthritis, Experimental / Q000188:drug therapy; D061945:Caspase Inhibitors; D004151:Dipeptides / Q000494:pharmacology*; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000188:drug therapy; D020382:Interleukin-18 / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D010081:Oxazolone / Q000633:toxicity; D011480:Protease Inhibitors / Q000494:pharmacology*; D062366:para-Aminobenzoates
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D061945:Caspase Inhibitors; D004151:Dipeptides; D020382:Interleukin-18; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D011480:Protease Inhibitors; D062366:para-Aminobenzoates; C520022:belnacasan; D010081:Oxazolone; D010129:4-Aminobenzoic Acid