Anti-TNFa Biologicals - The first biological approach to be approved for the treatment of steroid-refractory severe CD and fistulating disease was the chimeric anti-TNFa mAb, Infliximab (44). Even, as an i.v. infusion, this agent has had remarkable market penetration and has recently been additionally indicated as therapy for the maintenance of remission. However, there are a number of long term safety concerns associated with Infliximab, both in terms of the high degree of immunogenicity it elicits and that systemic TNFa suppression has been linked to an increased incidence of non-Hodgkin's lymphoma and opportunistic bacterial infections (eg. tuberculosis) (45). The efficacy observed with linfliximab has validated the inhibition of the TNFa axis in the treatment of IBD and, as a result, a number of other anti-TNFa agents are either approved or in development (Table 1), offering potential improvements in side effect, drug delivery and long term clinical efficacy. However, caution needs to be exercised as recent clinical data with etanercept, a human soluble TNF receptor-Fc fusion protein have been disappointing, raising the possibility that not all anti-TNFa approaches will have predictable levels of efficacy (28).
TNFa-converting enzyme (TACE) - From the clinical precedence set by inhibitors of the TNFa axis, the development of TACE inhibitors have emerged. TACE is a membrane-bound zinc endopeptidase and, unlike the action of anti-TNFa mAbs, small molecule TACE inhibitors exert their effects by limiting the shedding of soluble TNFa from its active membrane-bound precursor. The concept that TACE inhibition is potentially a small molecule alternative to the anti-TNFa biological agents has been recognized for a variety of inflammatory conditions, including IBD (46). A potential disadvantage, however, is that only the soluble form of TNFa is controlled by TACE inhibition and the membrane-bound form retains its activity. Nevertheless, ex vivo experiments have demonstrated that a TACE/MMP inhibitor, but not the MMP inhibitor Trocade (Ro-32-3555), effectively blocks TACE activity in mucosal biopsies taken from UC patients (47). Although the TACE inhibitor was not exemplified in this publication, there are several TACE inhibitors that have been described. The N-hydroxy formamide TACE inhibitor, GW-3333 (5), has been shown to be as effective as a neutralizing anti-TNFa antibody in a rat adjuvant arthritis model (48). GW-3333 has additional activity at other MMPs that could limit its utility as an oral agent, but, as measurable increases in MMP-1-3 activity also correlate with the destruction of mucosal tissue in IBD patients, a non-selective TACE/MMP inhibitor, engineered for topical delivery and low systemic exposure, could have significant advantages over both oral TACE and biological anti-TNFa approaches. While 5 is not very selective for TACE over other MMPs, compounds with better selectivity, such as 6 and 7, have been reported (49, 50). IK682, (7), is selective for TACE and has favourable pharmacokinetics in rat and dog (51). Optimisation of these lactam structures for improved cellular potency led to the clinical candidate (DPC-333/BMS-561392, 8) at the expense of some MMP selectivity (52). In single dose Phase I trials, 8 is well tolerated and has a short mean half-life at doses <80 mg but a longer half-life (6 h) at higher doses (53). Although long-term safety data have not yet revealed any problems with arthralgia or myalgia, these musculoskeletal side effects have been a common problem with non-selective hydroxamate-based MMP inhibitors (54).
Interleukin-1B Converting Enzyme (ICE) - IL-ip and IL-18 are up-regulated in colonic tissue from CD patients and play a pivotal role in effecting Th1 and macrophage responses; significantly, neutralisation of IL-18 activity ameliorates the inflammation observed in animal models of colitis (55, 56). IL-ip and IL-18 production is determined by the protease activity of the IL-ip converting enzyme, ICE/caspase-1.
While other small molecule approaches to IL-ip inhibition have been reported (57), ICE has received the most attention. Two distinct ICE inhibition strategies designed to mimic the YVAD cleavage sequence of pro-IL-ip have been described: irreversible inhibitors, characterized by 9, or reversible ones such as pralnacasan (10). Pre-clinically, chronic administration of dextran sodium sulfate (DSS) to ICE knockout mice fails to induce colitis, an effect accompanied by reduced cell activation in the draining mesenteric lymph nodes and a significant reduction in colonic IL-18, IFNy, and IL-1(3 (58). Pralnacasan, an orally active ICE inhibitor, is currently in Phase II development for RA. In an acute DSS-induced mouse model of colitis, pralnacasan administration (100 mg/Kg i.p, q.d.) resulted in significant amelioration of disease activity (59).
PDE4 - A decrease in intracellular cAMP following co-stimulation of CD3/CD28 is one of the key triggers for T-cell activation. PDE4 and PDE7 appear to be the predominant cAMP-dependent phosphodiesterases in inflammatory cells, and either inhibition of PDE4 activity or PDE7 expression reduces T-cell activation and the production of pro-inflammatory cytokines (60). The therapeutic potential of non-emetic PDE4 isotype-selective inhibitors for COPD and asthma has been advocated, but to date no compound has yet reached the market in spite of the fact that over a dozen inhibitors from a variety of structural series have advanced to clinical trials (59). Representative PDE4 inhibitors, including rolipram (H), cilomilast (12), roflumilast (13), arofylline (14). and lirimilast (15) and the full range of inhibitors along with new chemical series has recently been reviewed (61). In rodent models of colitis, efficacy for rolipram and arofylline has been reported. In particular, rolipram (5 mg/kg, b.i.d, i.p.) was able to halt the progression (but not the onset) of colitis in a DSS mouse model (62-64). The effect of rolipram in mice with existing DSS-induced colitis resulted in faster recovery after DSS discontinuation than for untreated animals. Structural differences in the reported series of PDE4 inhibitors notwithstanding, the common side effect of nearly all PDE4 inhibitors is emesis which narrows the therapeutic index. The development of non-emetic PDE4 inhibitors awaits a more complete understanding of the underlying causes of emesis or potentially through the design of novel PDE4 isotype-selective agents.
To circumvent the known side effects and short (2-3 h) half-life of rolipram in humans, a sustained release nanoparticle formulation that specifically targets the colon has been developed (65). In a rat TNBS-induced model of colitis, this formulation was as effective as dosing a rolipram solution (66). However, on discontinuation of solution dosing, treated animals relapsed, whereas the animals given nanoparticles showed only a slight increase in the severity of their clinical scores. Significantly, the nanoparticle-treated animals showed fewer side effects associated with systemic exposure than animals dosed with a rolipram solution, as judged by the established neurotropic indicators of grooming and forepaw shaking.
p38 - Similarly, against the known efficacy of 5-ASAs and glucocorticoids, a number of other intracellular targets that modulate the NF-kB pathway have emerged. One of the most well-progressed approaches is in the design of selective p38 MAPK inhibitors. p38 signals downstream of the IL-1(5 receptor and LPS/TLR to regulate, in part, the transcription/translation of pro-inflammatory cytokines, including IL-ip, IL-6 and TNFa (67-69). In vivo, p38 MAPK inhibitors have shown activity in both acute and chronic models of inflammation (70, 71). There have been equivocal data reported on the pre-clinical efficacy of the founding p38 inhibitor, SB-203580 (16), in a model of TNBS-induced colitis (72), In a separate study, 12 patients with severe CD were administered CNI-1493 (25 mg/kg/day i.v.), a tetra-guanylhydrazone, which is reportedly a dual p38/JNK inhibitor (73). Although treatment was only 12 days, 42% of patients were in clinical remission after 8 weeks and all but one patient showed endoscopic improvement. As p38 and JNK are known to be activated in the inflamed mucosa of IBD patients only the use of more selective p38 inhibitors will be able to de-convolute the relative importance of p38 in IBD. This is also an issue for the experiments conducted with the pyridyl-imidazole SB-203580, as the compound is less than 10-fold selective for p38a over JNK (74, 75). By comparison, the recently described pyrimdyl-imidazole p38 inhibitor SB-242235 (17) is reportedly much more selective and does not inhibit JNK up to 10 |xM (76). SB-242235 is also orally active and effective in models of LPS- and adjuvant-induced arthritis. Pharmacokinetic endpoints for SB-242235 have been described for pre-clinical species and the mean human half-life is reported to be 16.4 h (77). In a human ex vivo assay, greater than 75% inhibition of TNFa and IL-1 p expression was achieved after 3 h at doses greater than 150 mg (78).
At least two other p38 inhibitors have recently been reported to be in human clinical trials. BIRB-796 (18), a diaryl urea-based p38 inhibitor is in Phase II clinical trials for RA (79). Although BiRB-796 is reported to have excellent kinase selectivity, it is only so by virtue of the exquisite potency for p38a (Kd = 0.1 nM) as the IC50 for JNK inhibition is 0.1 nM (80). The low Kd is estimated to translate to a 23 hr off-rate and a long pharmacodynamic end-point, beyond the 6-10 hr elimination half-life (81). In a human endotoxemia model, inhibition of TNFa was observed with 50 mg doses of BIRB-796 (82). VX-745 (19) is another selective p38 inhibitor that has shown reductions in ACR20 response scores relative to placebo in a 12 week Phase II RA (83). While clinical trials have been suspended with VX-745, it would serve as a useful tool in establishing the role of p38 in IBD. Although detailed safety data is not available, a common reported issue with p38 inhibitors is the elevation of aspartate and alanine aminotransferase activity. Development of p38 inhibitors that are specifically delivered to the mucosal lining of the intestine for the treatment of IBD may avoid these unwanted effects in the liver.
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