Sphingosine-1-phosphate (S1P) is the endogenous ligand for the sphingosine-1-phosphate G-protein coupled receptors (S1P1-5). The interaction of S1P with the S1P receptors plays a fundamental physiological role in many processes including vascular stabilization, heart development, cancer angiogenesis and lymphocyte homing. Agonism of S1P1 has been shown to block lymphocyte trafficking from the thymus and secondary lymph nodes resulting in immunosuppression. As a result, agonists of this type hold promise as therapeutics for autoimmune disorders. The previously disclosed differentiated S1P1 modulator BMS-986104 demonstrated improved pre-clinical cardiovascular and pulmonary safety profiles as compared to earlier full agonists of S1P1, however, it possessed a human pharmacokinetic half-life (t<sub>1/2</sub>) in clinical trial that was longer than desired (&gt;15 days), and the formation of the active phosphate metabolite was found to be lower than expected. Optimization of this series through the incorporation of olefins, ethers, thioethers and glycols into the alkyl side chain afforded an opportunity to reduce the human t<sub>1/2</sub> and improve the in vivo formation of the active phosphate metabolite while maintaining efficacy as well as an improved safety profile.

Partial agonists of S1P1: Exploring side chain modifications of a bicyclic series to modulate the PK, PD, and safety profiles

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.