Inhibitors of Synthesis or Release - The disease modifying antirheumatic drugs (DMARDs) chloroquine (1), auranofin (2), sodium aurothiomalate (3) and dexamethasone (4), used clinically for the treatment of chronic rheumatoid conditions such as rheumatoid arthritis, have been reported to inhibit IL-1 synthesis (60). While both gold drugs 2 and 3 inhibited mitogen-induced IL-1 release from peripheral blood mononuclear cells (PBMC), only 2 inhibited both spontaneous release and LPS induced release (61). The mechanism of action of 4 was recently shown to be at two levels: jn vitro transcription assays with isolated nuclei from glucocorticoid treated cells show inhibition of IL-1 gene transcription, and kinetic studies involving pulse-labeling of mRNAs demonstrate a selective destabilization of the IL-ip mRNA (62).
Tenidap (5, CP-66,248) is an antiarthritic drug in clinical phase III trials, and has shown efficacy both in patients with osteo- and rheumatoid arthritis (RA) (63). Clinical improvement in RA
patients was observed by the second week of treatment. After 4 weeks of treatment at 40 to 120 mg daily dose, 5 was judged superior to placebo in all measures tested. This dual inhibitor of 5-lipoxygenase and cyclooxygenase (5-LO/CO) also inhibits the synthesis of both 17 kD IL-1 and 34 kD pro-IL-1 in LPS or zymosan stimulated murine peritoneal macrophages in vitro (64) and is reported to reduce IL-1 activity in the synovial fluid of rheumatoid arthritic patients by 35% in paired measurements of IL-1 from synovial fluid (65). Many analogs of 5 have been patented as antiinflammatory agents and analgesics (66).
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The tricyclic ylidene-acetic acid 6 is an antiarthritic, antipyretic and analgesic drug which is reported to block the acute phase reaction in animal models (67). jn vitro, 6 blocks the synthesis of prostaglandins from zymosan stimulated murine macrophages and inhibits the release of IL-1 a and IL-1 p from human monocytes and murine macrophages. Compound 6 and a series of its analogs, particularly the 2-chloro derivative, were recently patented as inhibitors of IL-1 release from human monocytes and mouse macrophages claiming clinical improvement in patients with psoriasis, periodontal disease and Alzheimers disease (68). Results from one clinical study of 6 in arthritic patients reported improvement in clinical measures of disease severity (67).
The dual 5-LO/CO inhibitor SK&F 86002 (7), has been reported to inhibit the synthesis of IL-1 in human monocytes and human synovial cells in a dose dependent manner (69-71). Examination of analogs showed no correlation between IL-1 inhibition and LTC4 inhibition in monocytes (71). Study of ibuprofen, phenidone and benoxaprofen in this assay demonstrated that neither selective CO, LO nor dual inhibition was sufficient for downregulation of IL-1 synthesis. The mechanism of action of 7 upon IL-1 production has been demonstrated to be mainly at the level of transcription of IL-1 mRNA in LPS stimulated human monocytes but may also involve a post-transcriptionai component (71,72). Both 7 and its sulfur replacement analog 8 significantly reduced both serum amyloid protein content and disease severity in the murine collagen arthritis model (73). These compounds and additional analogs 9,10 and H have been recently patented as IL-1 inhibitors (74-76).
The antioxidant and 5-LO inhibitor NDGA (nordihydroguaiaretic acid, 12) has been observed to inhibit IL-1 production by LPS stimulated monocytes in vjtro (69). Probucol (13), a hypocholesterolemic drug which possesses antioxidant activity, has been recently reported to inhibit the ex vivo release of IL-1 from LPS stimulated macrophages of mice pretreated orally with 100 mg/kg/day of drug (77,78). ]n vivo, 13 was observed to inhibit the fall in serum zinc levels induced by iv LPS administration (78). IL-1 induces the production of metallothionein by the liver, which then binds zinc and reduces unbound serum zinc levels (78). The inhibition of this LPS induced zinc lowering effect by 100 mg/kg of 13 dosed for 2 weeks is attributed as direct evidence for inhibition of IL-1 release (78). This Inhibition of IL-1 secretion is thought to contribute to the therapeutic effect of 13 in atherosclerosis; levels as low as 1 unit of recombinant IL-1 (3 induce the proliferation of aortic smooth muscle cells (79). Similarly, a group of antioxidants of diverse structure, disulfiram (14), 15 and 16 have been recently patented as Inhibitors of IL-1 release when dosed orally to CD-1 mice and assayed ex vivo (80). While no indication is given of in vitro inhibition for this group of antioxidants, 13 is specifically reported to have no direct in vitro effect between 10~3 and 10* (iM, thus the mechanism of IL-1 inhibition in these classes of antioxidants requires further clarification (78).
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