Anti Inflammatory Approaches

NFkB is a transcription factor that is rapidly activated in response to pro-inflammatory stimuli, infections, and physical and chemical stressors (Figure 1). NFkB participates in the induction of numerous immunoregulatory genes, whose products include pro-inflammatory cytokines, growth factors, chemokines, adhesion molecules, and enzymes that produce secondary inflammatory mediators. Activated nuclear NFkB is frequently detected at sites of inflammation and infection. Multiple pathways control the activation and translation of NFkB-dependent reporter genes: the IkB kinase (IKK) complex, p38 kinase, TGFfS-activated kinase (TAK-1), etc. (Figure 1). For some time, aberrant activation of the NFkB transcriptional pathway has been considered a major mechanism in the disease pathogenesis of IBD. When antisense constructs to silence the p65 NFkB subunit are introduced into the murine IL10 knockout model of colitis, the disease severity greatly improves.54 Evidence from a gut ischemic-reperfusion model55 also indicates that the NFkB pathway maintains mucosal barrier function, protection from reactive oxygen species, and apoptosis induced by inflammatory mediators. The modulation of the pathways that converge on NFkB is an important therapeutic avenue for attenuating inflammation.

6.28.8.2.1 Phosphodiesterase-4 (PDE4) inhibitors

Cellular levels of cyclic AMP (cAMP) regulate T cell activation and endothelial adhesion, the synthesis and release of pro-inflammatory cytokines (IFN-g, TNF-a, IL8, etc.) from macrophages and monocytes, and the generation of nitrous oxide and superoxide from neutrophils. PDE4A, PDE4B, and PDE4D are the predominant cAMP-hydrolyzing PDEs in most inflammatory cells, and their inhibition is associated with broad anti-inflammatory effects. The contribution of PDE7 activity to this process is now no longer considered significant.56 In the rat DSS model of colitis, the PDE4 inhibitors rolipram (9) (10mgkg_ 1, four times per day, intraperitoneally) and OPC-6535/Tetomilast (10) (1 mgkg _ 1, four times per day, orally) significantly reduce the extent of mucosal erosion, bleeding, and inflammation.57'58

There is tremendous structural diversity reported for PDE4 inhibitors,59 but, as a class, their therapeutic utility and clinical development had been historically dogged by dose-limiting nausea and emetic side effects. It is now believed that tolerance to PDE4 inhibitors is dependent on two components, the relative receptor subtype selectivity for PDE4B (anti-inflammatory) over PDE4D (emesis), and the plasma Cmax exposure. Cilomilast/SB-207499 (11), developed by GSK, and roflumilast/BY-217 (12) are both in phase III clinical trials for COPD. Cilomilast is more selective for PDE4D than the other subtypes, whereas roflumilast, and its major active metabolite N-oxide, are both more potent and do not discriminate between subtypes. Roflumilast is significantly better tolerated than cilomilast. Together, these data point to the potential clinical value of PDE4B selective inhibitors in inflammatory diseases, although neither agent has been assessed in patients with IBD. In contrast, tetomilast (25 or 50 mg per day orally for 8 weeks) has been assessed clinically in a phase II study with 186 UC patients.60 Clinical improvement (defined as a three-point reduction in disease activity index) was achieved by 55% and 48% of patients taking 25 and 50 mg tetomilast, respectively, compared with 40% of patients taking placebo. A significantly higher proportion of patients taking tetomilast had reduced rectal bleeding and entered disease remission than those on placebo. The selectivity of tetomilast for the PDE4 isotypes is unknown, but drug-related side effects (nausea) accounted for 8% withdrawals in the 50 mg group. The future medicinal chemistry challenge for IBD is to prise apart efficacy from emesis. This might be achieved by a number of strategies, either by identifying pharmacophores that distinguish the close sequence and structural homologies of PDE4B and PDE4D, or by the design of less central nervous system (CNS) penetrant inhibitors, or PDE4 inhibitors that act through a topical mode of action and have lower systemic exposure.

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

Get My Free Ebook


Post a comment