Inflammatory bowel disease (IBD) is a major medical issue impacting over 1 million patients in the United States. The global IBD therapeutics is anticipated to exceed $6.2 billion by 2017. IBD consists of 2 major disorders, Crohn’s disease and ulcerative colitis. Both are typified by severe, chronic inflammation of the gastrointestinal (GI) tract. Despite decades of research, disease pathogenesis remains poorly understood and there is no cure. The current standard of care focuses on disease management and mitigation of symptoms. Initial relief can be achieved with anti-inflammatories and corticosteroids, but severe of side effects prevent extended use. Longer term therapies include the immunomodulatordrugs and anti-TNF-α antibodies, but these options are not curative. Surgical intervention to remove diseased tissue is an option, but reoccurrence is high. Ultimately, curative therapeutic agents are necessary in order to fully address IBD.
Recent literature has linked IBD to dysregulation of 5-HT activity in the GI tract. Specifically, 5-HT7 receptor knockout mice display significant resistance to colitis induction in the DSS (dextran sulfate sodium) mouse model of IBD when compared to wild-type mice. In addition, the selective 5-HT7 receptor antagonist SB-269970 ameliorated colitis in acute and chronic DSS mouse models. Disease manifestation, histological damage, and cytokine levels were all reduced by SB-269970. These studies implicate the 5-HT7 receptoras a key player in IBD progression and indicate that suppression of 5-HT7 activity is a viable strategy for the treatment of IBD. We have identified novel 5-HT7 antagonists that have binding potencies and efficacy in the low nanomolarrange. In addition, our proof of concept lead compound, 170073, is efficacious in the DSS mouse model (10 mg/kg IP). We are currently identifying additional lead candidates suitable for in vivo efficacy assessment, pre-clinical study, and ultimately clinical evaluation for the treatment of IBD.