ADENOSINE 3 RECEPTOR AGONIST FOR TREATMENT OF COLITIS

Inotek Pharmaceuticals Corporation, Beverly MA

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Abstract

Agents that inhibit pro-inflammatory cytokine and chemokine expression may be effective therapeutics for inflammatory bowel disease (IBD). Inotek Corporation, a Massachusetts-based biopharmaceutical firm, is developing a novel class of compounds with potent anti-inflammatory activity. In this proposal, we present evidence that an agonist of the adenosine 3 (A3) receptor, N6-(3-iodobenzyl)-adenosine-5'-N- methyluronamide (IB-MECA) (1) reduces the production of multiple pro- inflammatory cytokines and chemokines, (2) enhances the production of the anti-inflammatory cytokine IL-10, (3) inhibits the expression of the inducible isoform of nitric oxide (NO) synthase (iNOS), an enzyme that is expressed in colitis and produces cytotoxic amounts of the free radical nitric oxide, and (4) protects in rodent models of shock and arthritis. Inotek now seeks Phase I NIH SBIR funding to establish the in vivo feasibility of IB-MECA as a novel anti-colitic therapeutic. The Specific Aim of this proposal is to determine the pharmacodynamic profile of a novel A3 agonist (IB-MECA) in a clinically-relevant rodent model of enterocolitis. We will establish proof-of-principle that IB-MECA is effective in a well- established rat model of enterocolitis produced by colonic instillation of trinitrobenzene sulfonic acid in ethanol (TNBS). IB-MECA will be administered per gavage at 3 dose levels TID in a randomized, blinded, post-insult paradigm for 4 days, the timepoint of peak injury in this model. Tissue samples will be obtained for evaluation of histologic correlates of mucosal injury, myeloperoxidase activity (a marker of neutrophil infiltration), F2-isoprostane and malondialdehyde concentration (markers of lipoperoxidation), pro-inflammatory cytokine and chemokine expression, and iNOS and nitrotyrosine immunoreactivity. Confirmation that IB-MECA is an effective anti-colitic agent in this experimental model will justify a Phase II application to support pre-clinical pharmaceutical testing (advanced toxicity determinations, pathology, stability, pharmacokinetics, in vivo primate studies), an investigational drug application to the FDA and Phase I clinical trial. PROPOSED COMMERCIAL APPLICATIONS: The market for a safe and effective novel therapeutic for inflammatory bowel disease would is in excess of $1 billion per annum in the US.