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6.28.8.2.3 p38 kinase inhibitors

The p38 family of protein kinases lie downstream of the IL1b receptor and LPS/TLR to regulate, in part, the transcription/translation of pro-inflammatory cytokines and other NFkB-dependent genes, including IL1b, IL6, and TNF-a (Figure 1). Since the discovery of the founding member, the pyridylimidazole SB-203580 (16), the development of potent and selective p38 kinase inhibitors has been an area of active research and clinical assessment.68 The dual p38/JNK tetra-guanylhydrazone inhibitor CNI-1493 (17) (25 mgkg_ 1 day_ 1, intravenously for 12 days) has been assessed in patients with severe CD,69 inducing clinical remission in five out of 12 patients at 8 weeks and endoscopic improvement in all but one patient. More potent and selective inhibitors have been developed from either the pyridylimidazole pharmacophore, such as SB-242235 (18), L-790070 (19), and a series of recently discovered bisamides, exemplified by 20 (p38a IC50 = 28nM) which is effective (30mgkg_ 1, orally) at reducing TNF-a production in Balb/c mice challenged with staphylococcal enterotoxin B.70 The most clinically advanced agents, Doramapimod/BIRB-796 (21)71 and VX-745 (22), have both demonstrated proof of concept in phase II trails for rheumatoid arthritis. BIRB-796 is an exceptionally high-affinity p38a kinase inhibitor (Kd = 0.1 nM), for which clinical trials in patients with CD are under way. Vertex and Kissei were developing VX-745, the pyrimido pyridazinone that selectively inhibits the a and b isoforms of p38 (IC50 = 10 nM and 220 nM, respectively), but not p38g (IC50>20 mM), for rheumatoid arthritis. Although VX-745 demonstrated excellent efficacy in inflammatory rheumatoid arthritis models (and by analogy activity in colitic models), VX-745 was also associated with neurological toxicity. Genetic deletion of p38a in mice results in embryonic lethality, and it is unclear whether the toxicity observed for VX-745 is mechanism or pharmacophore mediated. Further preclinical work is required to determine whether systemic or topical p38 inhibitors, which target the gut mucosa specifically and akin to the mode of action of budesonide over other glucocorticoids, have utility in the treatment of IBD.

Colitic Arthritis

6.28.8.2.4 Interleukin-1 p converting enzyme (ICE) inhibitors

The overproduction of active IL1b and IL18, observed in patients with IBD, is dependent on processing by the ICE/ caspase-1 protease. Chronic administration of DSS to ICE_/_ mice fails to induce colitis, an effect accompanied by reduced cell activation in the draining mesenteric lymph nodes and a significant reduction in colonic IL18, IFN-g, and IL1b.72 There are relatively few reported examples of selective ICE inhibitors. However, pralnacasan/VX-740 (23), designed on the peptide scaffold AcYVAD-CHO, is an ethyl-hemiacetal orally bioavailable prodrug ICE inhibitor currently in phase II development for rheumatoid arthritis. Once absorbed (reportedly, F = 43%), it is rapidly hydrolyzed to the active but reversible aldehyde protease inhibitor. In the acute DSS-induced mouse model of colitis, pralnacasan administration (50mgkg_ 1 twice daily intraperitoneally) resulted in significant reduction in disease activity.72 Similarly, VX-765 (24) is also under early clinical assessment for inflammatory conditions, 73 but clearly further development work on this class of agents is warranted on the basis of the preclinical and clinical data reported so far.

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