Our efforts towards the identification of partial agonists of S1P1 with differentiated safety profiles led to the discovery and clinical development of BMS-986104 (1) and BMS-986166 (2). With a goal of increasing the in vivo potency and further reducing the pharmacokinetic half-life (t1/2) of 1 and 2, SAR studies of aryl ether and thioether-derived bicyclic S1P1 partial agonists 3–6 were conducted. In this presentation, the effects of analogs 3–6 on the levels of lymphocyte reduction in the rat (the desired pharmacology) along with pulmonary and cardiovascular-related effects (undesired pharmacology) will be detailed. The projected safety profiles of select compounds were found to be superior to that of FTY720 and comparable to what was observed for 1 and 2, with notable reductions in t1/2.

Aryl ether and thioether-derived bicyclic S1P1 partial agonists: Optimization of the PK, PD and safety profiles through sidechain modifications

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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