(262) Identification of novel 5-HT7 antagonists with efficacy in animal models of IBD

Objective : Inflammation observed in Inflammatory Bowel Disease (IBD) is associated with increased serotonin (5-HT) signaling. We have previously demonstrated that 5-HT signaling via the 5-HT7 (5-HT7) receptor in the gastrointestinal (GI) tract is a key component of IBD disease progression. Our hypothesis is: blockade of 5-HT signaling via the 5-HT7 receptor with our novel, 5-HT7 subtype selective ligands will serve to reduce inflammation in IBD and lead to novel agents useful in the treatment of IBD.

Methods: Two novel, subtype selective 5-HT7 receptor antagonists (MC-170073 and MC-230078) with drug-like properties were evaluated in two widely accepted models of IBD. MC-17003 is a racemic mixture that was evaluated first via the I.P. route (10 mg/kg) in the acute and chronic DSS models to establish proof of concept. The "active" enantiomer, MC-230078 was then evaluated PO in the acute dextran sodium sulfate (DSS; 10mg/kg) mouse model and the CD4+CD45RBhigh T cells transfer mouse model (5mg/kg and 10mg/kg) of colitis.

Results: The compounds were administered I.P. in early studies of MC-0073 and orally for the later studies involving the enantiomer (MC-230078) to mice in each of the assays. Amelioration of intestinal inflammation, decreased histopathological damage, and lower levels of pro-inflammatory cytokines were observed in mice treated with both 5-HT7 antagonists (MC-170073 or MC-230078).

Conclusions: Our early lead 5-HT7 antagonist, 170073 (10mg/kg, IP), was shown to be efficacious in acute and chronic DSS mouse model while enantiomer, 230078 was shown to be efficacious in acute DSS (10mg/kg, PO) and T-cell induced colitis mouse models (5mg/kg and 10mg/kg, PO). Our data suggest that antagonizing GI 5-HT7 signaling may be a viable treatment option for the treatment of IBD.