Inflammatory bowel disease (IBD) is a major unresolved medical issue impacting over 1 million patients in the United States alone. As of 2011, the global IBD therapeutics market had an estimated value of over $4.8 billion, and it is anticipated that the market will grow to over $7.8 billion by the end of 2017. IBD consists of two major disorders, Crohn?s disease and ulcerative colitis, both of which are typified by severe and chronic inflammation of the gastrointestinal tract. Despite decades of research, disease pathogenesis remains poorly understood and there is no cure. The current standard of care for IBD focuses on disease management and mitigation of symptoms in order to minimize complications and patient suffering. Initial symptomatic relief may be achieved with anti-inflammatory corticosteroids, but long term therapy with these agents is not possible due to the severe of side effects. Longer term therapies for symptom suppression include the immunomodulator drugs and anti-TNF-? monoclonal antibody, but none of these options are curative, and disease related morbidity remains unacceptably high. 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 reports have linked IBD to dysregulation of 5-HT activity in the gastrointestinal tract. Specifically, TPH1-deficient mice exhibit significantly reduced IBD severity in mouse models (dextran sulfate sodium induced colitis and dinitrobenzene sulfonic acid induced colitis) as a result of decreased 5-HT in the gut. Artificial restoration of 5-HT in the gastrointestinal tract led to an increase in IBD severity in these models, strongly suggesting a key role for 5-HT in IBD. Similarly, attempts to induce colitis in mice lacking the 5-HT7 receptor led to significantly lower severity IBD than that observed in the wild type mice. Finally, the selective 5- HT7 receptor antagonist SB-269970 ameliorated acute and chronic DSS induced colitis in mice. Disease manifestation, histological damage, and pro-inflammatory cytokine levels were all reduced. This has been attributed to the suppression of 5-HT7 activity in colonic dendritic cells, which play a pivotal role in primary immune response and intestinal inflammation associated with IBD. These studies implicate the 5-HT7 receptor as a key player in the progression of IBD and indicate that suppression of 5-HT7 activity with a selective 5-HT7 antagonist is a viable therapeutic target for the treatment of IBD. We have identified novel 5-HT7 antagonists that have binding potencies and functional efficacy in the low nanomolar range. In addition, our initial proof of concept lead compounds 170073 and 230168 are efficacious in the acute and chronic DSS mouse model when dosed at 10 mg/kg IP, confirming the viability of our approach. Through the course of this program, we will expand the scope of our chemical equity by exploring the chemical space surrounding our lead series. These efforts will focus on developing novel, orally bioavailable, non-BBB penetrant lead compounds suitable for advanced in vivo efficacy studies.
Inflammatory bowel disease (IBD) is a major unresolved medical issue impacting over 1 million patients in the United States alone. The two major categories of IBD, Crohn?s disease and ulcerative colitis, have an incidence rate of 6.5 and 11 per 100,000 per year respectively. The current standard of care for IBD focuses on disease management and mitigation of symptoms in order to minimize complications and patient suffering; however, initial symptomatic relief with corticosteroids and longer term therapy with immunomodulators such as anti-TNF-? monoclonal antibody are not curative. Through the course of this program, we will discover new serotonergic modulating treatments that antagonize 5-Hydroxytryptamine receptor 7 (5-HT7) which has been implicated in Crohn?s Disease and Ulcerative Colitis.
