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A serious issue with troglitazone, which led to its withdrawal, is hepatotoxicity. Troglitazone both activates the pregnane X receptor, to increase CYP3A4 levels, and is also a CYP3A4 substrate and generates a reactive quinone metabolite. Rosiglitazone is also reported to be associated with liver, cardiovascular, and hematological toxicities as well as edema and weight gain. It is not clear whether any of these clinical adverse effects are mediated by the thiazolidinedione moiety, but many series of nonthiazolidenedione-containing and selective PPAR-g agonists have been described, such as the full agonists GW262570/Farglitazar (35) (previously in phase III trials), JTT-501/Reglitazar (36) previously in phase II/III trials), and 37,89 as well as the partial agonists 38 (EC50 = 3 nM, 24%)90 and 39 (EC50 = 250 nM, 40%).91 Further work is needed to establish the potential benefits of nonthiazolidenedione-containing PPAR-g agonists as well as the extent of agonism that can achieve efficacy in inflammation over effects on glucose and lipid homeostasis.

6.28.8.3 Targeting Lymphocyte Extravasation

The excessive recruitment of activated leukocytes is one of the core components in the inflammatory disease pathogenesis. Several therapeutic approaches have emerged in recent years that specifically target this process. The potential advantage of this approach compared with anti-inflammatory mechanisms is that, conceptually, by specifically restricting lymphocyte trafficking, the immune system can still function normally and is not immunosuppressed.

6.28.8.3.1 Integrin receptor antagonists

Mature lymphocytes continuously circulate between peripheral blood, lymphoid tissues, and organs. This process (homing) is needed both to develop an effective immune system and to maintain immune surveillance. The recirculation is not a random event, but a process that is controlled by a repertoire of integrins, glycoproteins, and chemokine receptors, expressed on leukocytes, and cell adhesion molecules, selectins, chemokines, and chemoattractants, expressed or secreted from specialized endothelium.

The very late antigen-4 (VLA-4), also known as integrin a4p1, is expressed on monocytes, T and B lymphocytes, basophils, and eosinophils, and is involved in the massive recruitment of granulocytes in different pathological conditions, including IBD, multiple sclerosis, and asthma. VLA-4 interacts with its endogenous ligand VCAM-1 during chronic inflammation, and blockade of VLA-4 /VCAM-1 interaction is a potential target for immunosuppression. The a4p7 integrin, expressed on populations of lymphocytes, is a unique GI tract homing signal and specifically interacts with MAdCAM expressed on specialized gut endothelium.92'93 At sites of inflammation, the expression of MAdCAM increases and this leads to an elevation in the recruitment of a4p7 lymphocytes. Blocking anti-MAdCAM or anti-a4p7 antibodies is effective in preventing rolling and adhesion of lymphocytes to the gut endothelium and reduce inflammation in animal models of colitis.93,94 These findings have led to the development of the humanized monoclonal antibodies natalizumab (anti-a4) and MLN02 (anti-a4p7), both of which have demonstrated clinical efficacy in patients with UC and CD (see 6.09 Neuromuscular/Autoimmune Disorders). By inhibiting the recruitment of key inflammatory cells these agents have the potential to improve IBD symptoms and rebalance oral tolerance without inducing systemic immune suppression. Two classes of VLA-4/a4p7 antagonists have so far been reported and reviewed95: b-amino acid derivatives containing a diaryl urea moiety (BIO-1211 (40) a4p1 IC50 = 4nM) and acylphenylalanine derivatives (examples including 41, a4p1 IC50 = 0.5 nM; a4p7 IC50 = 4.4 nM96, TR-14035 (42), a4p1 IC50 = 7 nM; a4b7 IC50 = 87 nM97, 43, a4p1 IC50 = 0.34 nM; a4b7 IC50 = 40.3 nM, F = 25%).98 Both series are Arg-Gly-Asp (RGD) mimetics and require a carboxylic acid to interact with a metal ion in the MIDAS domain on the integrin b-chain. With a few exceptions,98,99 however, these compounds tend to be of high molecular weight, have high metabolic clearance, are highly protein bound, and poorly bioavailable.

TR-14035 (10 mgkg_ \ intravenously) has been shown to block the binding of a4b7 + cells to MAdCAM in Peyer's patches by intravital microscopy,100 but like many of the compounds described from these series, TR-14035 is rapidly metabolized and poorly bioavailable. In contrast, the N-benzylpyroglutamyl 4-substituted-L-phenylalanine derivative, R411 (R00270608, Roche, IC50 = 0.37 nM), is currently under phase II clinical evaluation for asthma. The absolute oral bioavailability reported for R411 is approximately 27% and the terminal half-life is approximately 7.5 h, far higher than perhaps would have been anticipated from a high-molecular-weight acid.101 Although the structure-activity relationship (SAR) for the acylphenylalanine series is fairly well developed, with many literature examples of potent dual a4p1/a4p7 and selective a4p1 inhibitors, few molecules have been engineered that sufficiently discriminate a4b7 from a4b1. One exception,97 the trifluoromethansulfonamide (44), is nearly 400-fold selective for a4b7 relative to a4b1 (IC50 = 0.5 nM and 192 nM, respectively). Given the recent marketing withdrawal of natalizumab, due to fatal cases of progressive multifocal leukoencephalopathy in patients taking natalizumab and b-interferon,102 perhaps this also highlights the desire to achieve selectivity over VLA-4 and focus more effort on a4b7-selective inhibitors.

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