Targeting Lymphocyte Recruitment To The Inflamed Bowel
Nearly 30% of patients with steroid-refractory CD do not respond to infliximab. In addition, infliximab has not yet demonstrated clinical efficacy in treating UC (84). Other immunomodulatory approaches, such as recombinant IL-10 or IL-11 (Table 1), have also demonstrated modest clinical efficacy. Other approaches in development may better address these shortfalls in potency and side effect profiles.
LFA/ICAM - Common between CD and UC is the recruitment of large numbers of activated CD4+ lymphocyte to the gut lamina propria and associated lymphoid tissue (85). As a general mechanism of inhibiting T-cell recruitment, the LFA/ICAM interaction has received much clinical attention through ISIS-2302/alicaforsen. ICAM expression increases substantially in the disease state. ISIS-2302/alicaforsen is an anti-sense oligonucleotide that inhibits ICAM mRNA and expression, but the results of larger clinical trials have been disappointing (see Table 1) (86). However, the finding that lovastatin targets an allosteric site on LFA-1, inhibiting its binding to ICAM, has offered new opportunities for inhibiting this axis with small molecules. The development of additional mevinolin derivatives has been recently reviewed, but, of note, the modification of the integral lactone of lovastatin to cyclic carbamates, such as 20, improved affinity (IC50 = 50 nM) with equivalent activity as an anti-LFA mAb in some inflammatory models (87). Further series of compounds have developed from HTS screening, including the 5-substituted-3-phenylhydantoin derivates, such as BIRT-377, 21 (Kd = 25.8 nM) and the diaryl sulphides , represented by 22 (IC5o= 6 nM). There are little data reported on the potency of these compounds in vivo, although the encouraging effects of 22 on allergen-induced eosinophilia and LPS-induced neutrophil migration are suggestive that benefits might also be expected in animal models of colitis (88).
a4B7/MAdCAM - A specific system whereby lineages of lymphocytes bearing the expression of the a4p7 integrin were able to specifically home to the gut by engaging the mucosal addressin, MAdCAM has been described (89). MAdCAM is uniquely expressed on high endothelial venules supporting on the gut lamina propria and associated lymphoid tissue. The expression of MAdCAM increases tremendously at sites of inflammation, leading to an elevation in the recruitment of a4[37+ lymphocytes (90). Blocking anti-MAdCAM or anti-a4p7 antibodies are effective at blocking the rolling and adhesion of lymphocytes to the gut endothelium and reduce inflammation in animal models of colitis (13, 91). Humanised monoclonal antibodies natalizumab and LDP-02 that block the a4p7/MAdCAM interaction are in clinical development for UC and CD (Table 1). By inhibiting the recruitment of key inflammatory cells these agents have the potential to improve IBD symptoms and re-balance oral tolerance without inducing systemic immune suppression.
In terms of small molecule antagonists most of the work described in the literature has been directed at the related integrin a4pi (or very late antigen-4, VLA-4) and its interactions with VCAM (92-95). As a byproduct of this work on selective a4pi antagonists, compounds with good potency against a4p7 have also been generated. One of the earliest of these was BIO-1211 (23), with an IC50 <1uM against a4p7. Compound 24 is even more potent, with inhibition of a4pi (IC50 = 0.5 nM) and a4p7 (IC50 = 4.4 nM) (96). Another is the biphenylalanine derivative 25, TR-14035 (a4pi IC50 = 7 nM; a4p7 IC50 = 87 nM) (97). In the mouse, intravital
microscopy has been used to show that TR-14035 (10 mg/Kg i.v.) blocks the binding of a4(37+ cells to MAdCAM in Peyer's patches (98). Pharmacophore modeling has been used to optimize the selectivity of these dual a4pi/a4p7 antagonists, producing highly selective compounds with only minor changes to the structure of 25 (99). Compound 26 with the additional trifluoromethansulfonamide is nearly 400-fold selective for a4p7 relative to a4pi (IC50 = 0.5 nM, 192 nM, respectively). Although these integrin antagonists achieve desirable in vitro activities, as peptidomimetics they generally have poor bioavailability in vivo (96).
Delivery Systems - In reviewing IBD therapies, a discussion of delivery systems is essential. While the subject of colon-specific drug delivery has been reviewed elsewhere, it is worthwhile enumerating some of the current approaches and molecular properties that are desirable for drug delivery (100-102). Some of the major drug delivery strategies are: 1) pro-drug based approaches, such as that used by balsalazide and relying on bacterial azoreductase activity to release 5-ASA at the site of action; 2) pH sensitive coatings such as Eudragit®, made of aminoalkyl methacrylate copolymers that release the active agent at various pHs; 3) time release coatings that release the drug after a given period of time, usually determined by the coating thickness; 4) microflora methods that exploit the action of colon-specific enzymes (glycosidases, azoreductases) on the core coating. Each has their own limitations, including variations in the location of the disease within the gastrointestinal tract, differences in pH between the small intestine and the colon, and large differences in gastric retention times and colonic enzyme activity. With perhaps the exception of PDE4, none of the molecules for the newer approaches discussed herein have been specifically designed to work with a delivery system. Of the approaches described above, TACE, ICE and a4p7 inhibitors are pre-disposed for use with delivery systems as they rely on peptidomimetic antagonists. The disadvantages of a peptidomimetic for oral drugs (high clearance and poor absorption) are potential advantages for topical or locally delivered therapy - less potential for side effect due to systemic exposure. The molecule will require a degree of epithelial absorption and the little drug that does enter systemic circulation will have to be rapidly metabolised to pharmacologically inactive, non-toxic metabolites. While many of these attributes are intrinsic to a peptidomimetic, approaches such as PDE4 and p38 are still amenable to local delivery, a strategy that could overcome some of the safety and toxicity concerns associated with these targets. Indeed, research programs that search for orally bioavailable agents readily identify compounds with the desired biological properties, but with very short systemic half-lives and/or poor absorption. If not, building in metabolic liabilities into molecules and reducing absorption by adding molecular weight and/or polar groups is something that can be achieved with regularity by medicinal chemists. In the case of p38, the large molecular weight (505), lipophilic (ClogP= 5.5), potent (p38a IC50 = 0.1 nM), and selective inhibitor, L-790,070 (27) may be a good starting point (103).
Summary IBD is a highly morbid condition where, despite recent innovations, significant unmet medical need remains. The development and approval of Infliximab has not only been a valuable addition to the armamentarium of physicians, but has validated a pathway which may in the future prove highly exploitable with small molecules. A number of generic anti-inflammatory or immunomodulatory pathways have been identified and the use of imaginative medicinal chemistry or pharmaceutical science may allow their power to be harnessed in such a way as to ameliorate the impact of side effects. In addition, emerging data from a variety of novel biological agents may reveal a number of new targets, thus opening a new chapter in therapy for this problematic condition.
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