Tumor necrosis factor-a inhibitors

Two remarkable successes of cytokine therapy are the treatment of multiple sclerosis with interferon-p and the treatment of rheumatoid arthritis and inflammatory bowel disease with tumor necrosis factor-a inhibitors. 

Etanercept is a fully human dimeric fusion protein composed of human TNF-a p75 receptor fused to the Fc portion of human IgG 1.41 It acts as a tumor necrosis factor-a (TNF-a) inhibitor by binding to and inactivating TNF-a, thus preventing interactions with its cell surface receptors.41 This agent is useful for chronic moderate to severe plaque psoriasis and for psoriatic... 

Compounds 674-676 are potent orally bioavailable inhibitors of tumor necrosis factor-a (TNF-a) production <2004BML4267, 2004JME2724>. 

NO acts as an autocrine factor that mediates HIV-1 replication as at the molecular level, NO seems to stimulate long-terminal repeat-mediated transcription [125]. It was noted that exogenous NO increases replication of HIV-1 T-tropic isolates in primary T cells or T-cell lines, and inhibitors of iNOS partly block HIV-1 replication, especially that induced by tumor necrosis factor a [125]. The contrasting effects of exogenous NO, particularly NO donors, may depend on the type of NO donors, their releasing kinetics, and the dose used in the study design. 

ASPIRIN AND OTHER NATURAL INHIBITORS OF TUMOR NECROSIS FACTOR-a PRODUCTION, SECRETION,... 

The presence of tumor necrosis factor a directly leads to apoptosis via interaction with the tumor necrosis factor receptor, one of a class of receptors referred to as death receptors. NF-kB, which must enter the nucleus to initiate apoptosis, is a transcription factor sequestered in the cytoplasm by inhibitor of kB (IkB). The binding of TNFa to its receptor leads to the ubiquitin-dependent proteolysis of IkB, allowing NF-kB to enter the nucleus. The activation of apoptosis results directly from the stimulation of NF-kB, a transcription factor whose phosphorylation is controlled by vanadium compounds. In a global gene expression study, it was found that diabetes increased the formation of IkB, whereas vanadium compound treatment lowered the production of this inhibitor [101]. The activation of the TNFR also activates the caspase proteins, a class of proteases that cleave proteins after specific aspartate residues. 

A small-molecule inhibitor of tumor necrosis factor a, a protein involved in inflammatory diseases such as rheumatoid arthritis, has been identified <2005SCI1022>. Direct inhibition by the commercial biological agents Enbrel and Remicade has produced major advances in rheumatoid arthritis treatment and validated extracellular inhibition of this proinflammatory cytokine as an effective therapy. The new inhibitor 35 is composed of trifluoromethylphenyl indole and dimethylchromone moieties linked by a dimethylethylenediamine spacer. 

An X-ray crystal structure of 35 with tumor necrosis factor a revealed that the inhibitor binds with the intact biologically active trimer and accelerates subunit disassociation of one of the three subunits in the protein, rapidly inactivating the cytokine. Interestingly, 35 is able to access the normally buried interior of the tumor necrosis factor a trimer to form a complex with two of the subunits. The surprising results should help with the identification of other small-molecule inhibitors that inactivate multimeric proteins via a rapid predissociation-independent subunit dissociation process. 

Sheppeck JE, Gilmore JL, Yang A et al (2007) Discovery of novel hydantoins as selcective non-hydroxamate inhibitors of tumor necrosis factor-a converting enzyme (TACE). Bioorg Med Chem Lett 17 1413-1417... 

Wagner TE, Huseby ES, Huseby JS. Exacerbation of Mycobacterium tuberculosis enteritis masquerading as Crohn s disease after treatment with a tumor necrosis factor-alpha inhibitor. Am J Med 2002 112(l) 67-9. 

Inhibitors of Bacterial Cell Wall Biosynthesis. Interestingly, iminoalditol 81 (Figure 9.26) was found active against the Mycobacterium avium complex in an infected macrophage model at 4 p.g/ml [212]. Furthermore, this compound increased tumor necrosis factor a (TNFa) production in the infected cells. 

Eight novel 2-(2,6-dioxopiperidin-3-yl)phthalimidine EM-12 dithiocarbamates 9 and 10, N-substituted 3-(phthalimidin-2-yl)-2,6-dioxopiperidines 11-14, and3-substituted2,6-dioxopiperidines 16 and 18 were synthesized as tumor necrosis factor-a (TNF-a) synthesis inhibitors. The pharmacological focus of these compounds is toward the development of well-tolerated agents to ameliorate neuroinflammation in AD, Parkinson s disease, and other neurodegenerative/inflammatory disorders [512],... 

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