Novel 5-HT7 Antagonists for the treatment of inflammatory bowel disease

Inflammatory bowel diseaseIBDis a major unresolved medical issue impacting overmillion patients in the United States aloneAs ofthe global IBD therapeutics market had an estimated value of over $billionand it is anticipated that the market will grow to over $billion by the end ofIBD consists of two major disordersCrohn s disease and ulcerative colitisboth of which are typified by severe and chronic inflammation of the gastrointestinal tractDespite decades of researchdisease pathogenesis remains poorly understood and there is no cureThe current standard of care for IBD focuses on disease management and mitigation of symptoms in order to minimize complications and patient sufferingInitial symptomatic relief may be achieved with anti inflammatory corticosteroidsbut long term therapy with these agents is not possible due to the severe of side effectsLonger term therapies for symptom suppression include the immunomodulator drugs and anti TNFmonoclonal antibodybut none of these options are curativeand disease related morbidity remains unacceptably highSurgical intervention to remove diseased tissue is an optionbut reoccurrence is highUltimatelycurative therapeutic agents are necessary in order to fully address IBDRecent literature reports have linked IBD to dysregulation ofHT activity in the gastrointestinal tractSpecificallyTPHdeficient mice exhibit significantly reduced IBD severity in mouse modelsdextran sulfate sodium induced colitis and dinitrobenzene sulfonic acid induced colitisas a result of decreasedHT in the gutArtificial restoration ofHT in the gastrointestinal tract led to an increase in IBD severity in these modelsstrongly suggesting a key role forHT in IBDSimilarlyattempts to induce colitis in mice lacking theHTreceptor led to significantly lower severity IBD than that observed in the wild type miceFinallythe selectiveHTreceptor antagonist SBameliorated acute and chronic DSS induced colitis in miceDisease manifestationhistological damageand pro inflammatory cytokine levels were all reducedThis has been attributed to the suppression ofHTactivity in colonic dendritic cellswhich play a pivotal role in primary immune response and intestinal inflammation associated with IBDThese studies implicate theHTreceptor as a key player in the progression of IBD and indicate that suppression ofHTactivity with a selectiveHTantagonist is a viable therapeutic target for the treatment of IBDWe have identified novelHTantagonists that have binding potencies and functional efficacy in the low nanomolar rangeIn additionour initial proof of concept lead compoundsandare efficacious in the acute and chronic DSS mouse model when dosed atmg kg IPconfirming the viability of our approachThrough the course of this programwe will expand the scope of our chemical equity by exploring the chemical space surrounding our lead seriesThese efforts will focus on developing novelorally bioavailablenon BBB penetrant lead compounds suitable for advanced in vivo efficacy studies Project Narrative Inflammatory bowel diseaseIBDis a major unresolved medical issue impacting overmillion patients in the United States aloneThe two major categories of IBDCrohn s disease and ulcerative colitishave an incidence rate ofandperper year respectivelyThe current standard of care for IBD focuses on disease management and mitigation of symptoms in order to minimize complications and patient sufferinghoweverinitial symptomatic relief with corticosteroids and longer term therapy with immunomodulators such as anti TNFmonoclonal antibody are not curativeThrough the course of this programwe will discover new serotonergic modulating treatments that antagonizeHydroxytryptamine receptorHTwhich has been implicated in Crohn s Disease and Ulcerative Colitis