Info

6.28.8.4 Miscellaneous Mechanisms

6.28.8.4.1 Macrophage migration inhibitory factor antagonists

Levels of the pro-inflammatory cytokine macrophage migration inhibitory factor (MIF) are elevated in IBD patients. Transgenic animals which overexpress MIF are more susceptible to DSS-induced colitis,135 and either antibody blockade of MIF or genetic depletion in mice significantly ameliorates the DSS-induced inflammatory response in mice.136 MIF-deficient macrophages are hyporesponsive to LPS, show reduced activation of NFkB and the production of TNF-a, an effect which appears to be in part due to a downregulation of TLR4.

MIF possesses the unique ability to catalyze the tautomerization of D,L-dopachrome methyl esters into their corresponding indole derivatives. Compounds that block the active site either inhibit MIF activity directly or may force MIF into a conformation which prevents its binding to CD74.137 Despite the large structural diversity of MIF tautomerase inhibitors,138 few compounds appear to have been studied in animal models of disease. One ISO-1, compound 64,139 is a reportedly selective MIF tautomerase inhibitor (IC50b7 mM), which when administered to SDZ-treated mice (1mg per mouse per day intraperitoneally), markedly reduced clinical and histopathological features of diabetes (hyperglycemia and insulitis), to an extent that was comparable with that of an anti-MIF antibody.140 A number of MIF inhibitor candidates (AVP-13546, AVP-13748) are being clinically evaluated. When given orally to DSS-treated mice, AVP-13748 was effective at reducing the inflammation.141 The structure of AVP-13748 is currently not known but may be one of a series of quinoline 3-carbonitriles as recently claimed.142

6.28.8.4.2 TRPV1 antagonists

One of the symptoms in IBD is abdominal pain. Additional neurogenic mechanisms have been also implicated in the induction of IBD. For instance, substance P receptors exhibit dramatic increases in binding in the colons of both CD and UC patients. TRPV1 is a nonselective cation channel, expressed on nerve terminals of intrinsic and extrinsic afferent neurons innervating the GI tract. TRPV1 plays a key role in the detection of noxious painful stimuli such as acid and heat, and TRPV1 _'_ mice have impaired inflammatory thermal hyperalgesia. Immunoreactive TRPV1 fibers increase in the submucosal plexus of diseased IBD tissue. On DSS-induced inflammation in Balb/c mice, the TRPV1 antagonist capsazepine (65) (2.5mgkg_ 1, twice daily intraperitoneally), significantly reduced the severity of inflammation and epithelial damage.143 Capsazepine was the first competitive TRPV1 antagonist identified, but since this discovery, several other series of compounds have been identified. Compounds such as A-425619 (66), which is 25-to 50-fold more potent at blocking TRPV1 activation (IC50 = 5 nM) than capsazepine,144 and GR-705498 (67) (pKB~ 7.6),145'146 which are more druglike, have been described and warrant further preclinical evaluation in IBD models.

The observation that blockade of TRPV1 channels appears to be effective at reducing colitic inflammation opens up a number of other avenues, including the modulation of afferent activity by tetrodotoxin-resistant Na channel blockers, calcitonin gene-related peptide receptor antagonists, substance P and neurokinin receptor antagonists, and neuropeptide Y receptor modulators, many of which have already been implicated in nociception and neurogenic inflammation, as well as attenuating DSS-induced colitis,147'148 but for which the limit of this review cannot cover.

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Biographies

Nick Pullen graduated in biochemistry and chemistry and completed his PhD in G protein-coupled receptor signaling from the University of Southampton. From there he moved to the Novartis-funded Friedrich Miescher Institute in Basel, to pursue postdoctoral studies on signaling mechanisms involved in diabetes and oncology. He joined the Pfizer Gastrointestinal therapeutic area in 1999.

Jeremy D Gale has 17 years pharmaceutical industry experience in Discovery and Exploratory Development. He graduated in pharmacology and completed his PhD in pharmacology and neuroscience from the University of London. Jem commenced his career with Glaxo in 1988 to work in gastrointestinal pharmacology, ultimately leading their Discovery biology programs in reflux disease, irritable bowel syndrome, and emesis. He joined Pfizer in 1995 to lead Discovery Biology's Gastrointestinal research team and moved into Exploratory Clinical Development in 2002.

© 2007 Elsevier Ltd. All Rights Reserved Comprehensive Medicinal Chemistry II

No part of this publication may be reproduced, stored in any retrieval system or transmitted ISBN (set): 0-08-044513-6 in any form by any means electronic, electrostatic, magnetic tape, mechanical, photocopying, recording or otherwise, without permission in writing from the publishers ISBN (Volume 6) 0-08-044519-5; pp. 613-642

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