Novel HT Antagonists for the treatment of inflammatory bowel disease

Inflammatory bowel disease IBD is a major unresolved medical issue impacting over million patients in the United States alone As of the global IBD therapeutics market had an estimated value of over $ billion and it is anticipated that the market will grow to over $ billion by the end of 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 severe side effects Longer term therapies for symptom suppression include the immunomodulatory 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 in Crohn s disease Ultimately curative therapeutic agents are necessary in order to fully address IBD Recent literature reports have linked IBD to dysregulation of HT activity in the gastrointestinal tract Specifically TPH 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 HT in the gut Artificial restoration of HT in the gastrointestinal tract led to an increase in IBD severity in these models strongly suggesting a key role for HT in IBD Similarly attempts to induce colitis in mice lacking the HT receptor led to significantly lower severity IBD than that observed in the wild type mice Finally the selective HT receptor antagonist SB 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 HT activity in colonic dendritic cells which play a pivotal role in primary immune response and intestinal inflammation associated with IBD These studies implicate the HT receptor as an important player in the progression of IBD and indicate that suppression of HT activity with a selective HT antagonist is a viable therapeutic approach for the treatment of IBD We have identified novel selective HT antagonists that have binding potencies and functional efficacy in the low nanomolar range In addition our initial proof of concept lead compound is efficacious in the acute and chronic DSS mouse models when dosed at mg kg IP confirming the viability of our approach As minimization of BBB penetration remains a main focus of the program we have previously selected the spiro sulfonamide as a test case for the correlation of CNS penetration and TPSA Preliminary PK data on this compound demonstrated a decrease in CNS penetration validating this 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 and develop additional novel scaffolds These efforts will focus on developing novel orally bioavailable lead compounds exhibiting minimal CNS penetration that are suitable for advanced in vivo efficacy studies as part of a phase SBIR STTR program Project Narrative Inflammatory bowel disease IBD is a major unresolved medical issue impacting over million patients in the United States alone The two major categories of IBD Crohn s disease and ulcerative colitis have an incidence rate of and per 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 Hydroxytryptamine receptor HT which has been implicated in Crohn s Disease and Ulcerative Colitis