Agonism of the sphingosine-1-phosphate family of G-protein coupled receptors (S1PRs) gained validation as a therapeutic approach for treating multiple sclerosis with the approval of FTY720 (Gilenya) for the relapsing remitting form of this disease. FTY720 is a pro-drug, whose metabolically activated phosphate form (FTY720-P) is a non-selective S1PR agonist. Activation of S1P1 by FTY720-P has been linked to its beneficial immunomodulatory properties, whereas agonism of S1P3 was initially associated with several safety issues, such as cardiovascular and pulmonary effects (transient reduction in heart rate, atrioventricular conduction issues, mild but sustained elevation of blood pressure, and decreased pulmonary function). Subsequent clinical evaluation of S1P3-sparing S1P1 agonists, of both the pro-drug class as well as direct-acting agonists (those which do not require bio-activation), demonstrated that removing activity on S1P3 did not eliminate the liabilities. Our initial research, which focused on selective, direct-acting compounds with full agonism at S1P1, led to the identification of advanced compounds that had preclinical liability profiles similar to FTY720. Herein, we detail our pursuit of compounds with improved safety, in which we focused on S1P1 agonists that showed differentiated G-protein coupled signaling relative to FTY720-P and earlier full agonists. The search for S1P1 modulators that function as biased ligands required a shift from the direct-acting class to the pro-drug class of agonists (active phosphate metabolite) and resulted in the identification of BMS-986104. BMS-986104 produced robust, dose-dependent lymphopenia and maintained efficacy comparable to that of full agonists in animal models of human disease. The compound is readily differentiated from FTY720 and other clinical-stage S1P1 agonists as it shows improved pulmonary and cardiovascular (CV) safety in preclinical models. The human relevance of the preclinical assays was of key importance, particularly for CV effects, as rodent-based predictions had been found to correlate poorly with human CV profiles for S1P agonists. Utilization of a CV safety screen based on cultured human cardiomyocytes derived from inducible pluripotent stem cells eliminated concerns of cross-species differences. Based on the favorable efficacy and safety profile, BMS-986104 was advanced to clinical evaluation.

Discovery of BMS-986104: Moving from direct-acting, full agonists to pro-drug, partial agonists in the identification of a differentiated S1P1 modulator with an improved safety profile

253rd National Meeting (2017)

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