Interleukin-1/? converting enzyme inhibitors

The application of multiple reaction parameters executed in a parallel array format has been used to expedite the identification of optimal conditions for the synthesis of a collection of almost 600 new interleukin-1/ converting enzyme inhibitors [89]. The reaction in question was the problematic conversion of a / -tert-butyl aspartic acid bromoethylketone to the corresponding acyloxyketone (Scheme 2.63). The study en-... 

Levels of cytoplasmic oligonucleosomal DNA (cell death detection enzyme-linked immunosorbent assay) were significantly enhanced for chryso-tUe (3-25 pg/ml) and crocidolite (25-75 pg/ml) in a dose-dependent manner, a process that was inhi-bitable by 10 pM Z-Val-Ala-Asp fluoromethyl ketone, an interleukin-converting enzyme inhibitor (Hamilton et al. 1996). 

The cysteinyl proteases include papain calpains I and II cathepsins , H, and L proline endopeptidase and interleukin-converting enzyme (ICE) and its homologs. The most well-studied cysteinyl protease is likely papain, and the first x-ray crystallographic structures of papain [193] and a peptide chloromethylketone inhibitor-papain complex [194] provided the first high resolution molecular maps of the active site. Pioneering studies in the discovery of papain substrate peptide-based inhibitors having P, electrophilic moieties such as aldehydes [195], ketones (e.g., fluoromethylketone, which has been determined [196] to exhibit selectivity for cysteinyl proteases versus serinyl proteases), semicarbazones, and nitriles are noteworthy since 13C-NMR spectro-... 

Warmus et al. (121) recently reported the multivariate optimization of reaction conditions for the synthesis of a known class of ICE (interleukin-ip converting enzyme) inhibitors, represented by compound 9.70. The structure of the compound and the synthetic route, starting from the key bromide intermediate 9.71, are reported in Fig. 9.29 (the acetylvaline moiety of 9.70 was replaced during the optimization with an Fmoc carbamate). 

Severe hypotension within hours after interleukin-3 injection has been observed in three of 26 patients treated with angiotensin-converting enzyme inhibitors (SEDA-19, 340). Indirect synergy between ACE and interleukin-3 on nitric oxide production was suggested to be involved. 

The described work has also significant impact on the design of inhibitors for other enzymes. The first published nonpeptidic inhibitors of the cysteine protease interleukin converting enzyme (ICE) have been designed following the Zeneca approach [12]. Similarly, thrombin inhibitors have recently been disclosed that were designed along the same lines [13]. 

Dercksen MW, Hoekm an K, Visser JJ, ten Bokkel Huinink WW, Pinedo HM, Wagstaff J. Hypotension induced by interleukin-3 in patients on angiotensin-converting enzyme inhibitors. Lancet (1995) 345, 448. 

Fig. 1. Modulation of apoptosis by v-FLIP and v-Bcl-2. v-FLIPs specifically inhibit apoptosis mediated by death receptors. v-lCA specifically targets caspase-8 and inhibits its activation. v-Bcl-2 and vMIA inhibit those apoptotic pathways that are signaled through mitochondrial release of cytochrome c. FADD, Fas-associated death domain FLICE, FADD-like interleukin-converting enzyme CARD, cas-pase-recruiting domain PTPC. permeability transition pore complex FLIP, FLICE-inhibitory protein vie A, viral inhibitor of caspase 8-induced-apoptosis MIA. viral mitochondrial inhibitor of apoptosis Apcif-l, apoptotic protease-activating factor 1...

Porco et al. [4] reported a synthesis of the interleukin-lfS-converting-enzyme inhibitor EI-1941-2 (9) using Bobbitt s reagent 10 (Scheme 9.2). In this synthesis, the key step is the selective oxidation of primary alcohol 5 to give the corresponding aldehyde 6, which undergoes Gtr-electrocyclization to provide 7 followed by oxidation to yield a-pyrone 8 in 58% yield. The compound 8 was further converted into the target molecule 9 in a few steps. 

This ceramide-mediated apoptosis was shown to be inhibited by the simultaneous addition of PKC activators (Ni et at, 1994 Obeid et al, 1993), implying that PS may activate the ceramide-mediated apoptotic pathway. However, the inhibitors of interleukin-1 converting enzyme (ICE)-like proteases (Caspase), such as tosyl-L-lysine chloromethyl ketone (TLCK), and tosyl-L-phenylalanine chloromethyl ketone (TPCK) which inhibit ceramide-mediated apoptosis, had no effect on PS-induced apoptosis (Figure 4). Thus, PS-induced apoptotic pathway appears to be distinct from that mediated by ceramide. Further studies are required to clarify the molecular mechanisms underlying the PS-induced apoptosis. 

Hara H, et al. Inhibition of interleukin Ibeta converting enzyme family proteases reduces ischemic and excitotoxic neuronal damage. Proc. Natl. Acad. Sci. U. S. A., 1997 94 2007-2012. Schotte P, et al. Non-specific effects of methyl ketone peptide inhibitors of caspases. FEBS Lett. 1999 442 117-121. 

Okamoto Y, et al. Peptide based interleukin-1 beta converting enzyme (ICE) inhibitors synthesis, structure activity relationships and crystallographic study of the ICE-inhibitor complex. Chem. Pharm. Bull. 1999 47 11-21. 

Wannamaker W, et al. (S)-l-((S)-2- (l-(4-amino-3-chloro-phe-nyl)-methanoyl)-amino -3,3-dimethyl-butanoy l)-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 antiinflammatory activities by inhibiting the release of IL-lbeta and IL-18. J. Pharmacol. Exp. Ther. 2007 321 509-516. 

Peptidomimetic modifications of the tet-rapeptide sequence have led to the conforma-tionally constrained compound (69)as a selective inhibitor of caspase-1 or interleukin-1 converting enzyme (ICE) as potential anti-inflammatory compounds (131). Recently, new non-peptide peptidomimetic diphenyl ether sulfonamides have been described as novel lead structures (70) (Fig. 15.32) (132). 

Another approach is the inhibition of the TNF-converting enzyme (TACE), which converts proTNF into its mature, proinflammatory form. Also, numerous inhibitors of P38 and Erk-MAP kinases have been synthesized and some have reached the clinical trial stage. MAP-p38 kinase occupies a central role in the signaling network responsible for the up-regulation of proinflammatory cytokines like interleukin 1 and TNFa. The pathway of Erk-MAP kinase is often up-regulated in human tumors and as such represents an attractive target for the development of anticancer drugs. ... 

Ray, C.A., Black, R.A., Kronheim, S.R., Greenstreet, T.A., Sleath, RR., Salvesen, G.S. and Pickup, D.J. (1992) Viral inhibition of inflammation cowpox virus encodes an inhibitor of the interleukin-1 beta converting enzyme. Cell 69 597-604. 

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