Metabolite profiling of novel 5HT4PA in monkey plasma suggested possible active moieties in addition to the parent molecule in monkey plasma. This led us to a plausible iminium metabolite [M2  ] demonstrating activity at the 5HT4 receptor. Understanding the formation of this active metabolite in humans was important a) to support receptor occupancy projections in the clinic and b) to address MIST (Metabolites In Safety Testing) strategy for the program, going forward. Hence, the human plasma obtained from subjects administered a single dose of 40 mg, P.O. of 5HT4PA, was analyzed, fractionated and tested for M2  ; the results of this analysis demonstrated a large abundance of M2  in human plasma, relative to the parent. Application of semi-quantitative analysis of the metabolite in humans and pre-clinical species ensured coverage of this new metabolite in multiple dosing studies up to projected efficacious doses of the parent at 15 mg, Q.D., without significant efforts on metabolite synthesis. The current approach has played a significant role in accelerating timelines towards initiation of POC studies without a significant lag (6-8 months) during the late stage development of this program. In the meantime, an effort to synthesize a standard of the metabolite, in a diasteromeric mixture reflective of that in human plasma, was accomplished using microbial biosynthesis. This permitted measurement of the M2  at the target and off-target potencies, and plasma protein binding, and these values were used to estimate contribution to receptor occupancy at 5HT4 receptor. Current availability of authentic standard of metabolite M2  can support simple in vitro studies to understand the formation/clearance/accumulation of the circulating M2  ; in addition, development of the pre-clinical and clinical GLP assay will help us understand the ivivc of M2  pharmacokinetics in humans and pre-clinical species. Thereby a mass balance study may be deferred to post-POC.

Identification of a disproportionate metabolite of a novel 5HT4 partial agonist (5HT4 PA): Adherance to the MIST strategy by application of old tools using new approaches

246th National Meeting (2013)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.