Identification and Preclinical Pharmacology of BMS-986104: A Differentiated S1P₁ Receptor Modulator in Clinical Trials

Abstract

Clinical validation of S1P receptor modulation therapy was achieved with the approval of fingolimod (Gilenya, 1) as the first oral therapy for relapsing remitting multiple sclerosis. However, 1 causes a dose-dependent reduction in the heart rate (bradycardia), which occurs within hours after first dose. We disclose the identification of clinical compound BMS-986104 (3d), a novel S1P 1 receptor modulator, which demonstrates ligand-biased signaling and differentiates from 1 in terms of cardiovascular and pulmonary safety based on preclinical pharmacology while showing equivalent efficacy in a T-cell transfer colitis model. KEYWORDS: GPCR, S1P1, S1P3, biased signaling L ymphocyte infiltration from blood into sites of inflammation is critical to the pathogenesis of autoimmune diseases and allograft rejection. Gilenya (FTY720, 1) blocks lymphocyte migration through sequestration of lymphocytes in the thymus and secondary lymphoid organs, leading to a marked lymphopenia. 1 Compound 1 is a pro-drug; its phosphorylated form, FTY-P (1-P), binds four out of the five S1P receptors (S1P-1, 3, 4, 5) and elicits a full agonist response in functional assays such as GTP-S binding, ERK phosphorylation, cAMP, and calcium mobilization. Among these four receptors, S1P 1 has been shown to be critically involved in lymphocyte trafficking and agonism of this receptor is responsible for the peripheral blood lymphopenia believed to be key to the efficacy seen with 1. 2,3 Clinical studies have demonstrated a side effect profile of 1 that includes cardiovascular effects (transient bradycardia, sustained blood pressure elevation) as well as a decline in pulmonary function. 4 In rodent studies, S1P 3 activity was shown to play a role in some of the observed acute toxicity of nonselective S1P receptor agonists, including bradycardia, hypertension, and bronchoconstriction. 5,6 As agonism of S1P 3 does not appear to contribute to efficacy, the identification of S1P 1 agonists sparing of S1P 3 has been a primary emphasis of many research programs in this area. 7 However, clinical studies with S1P agonists with selectivity for S1P 1 over S1P 3 have suggested that in humans the heart rate reduction effects are controlled at least in part through agonism of S1P 1 . 8 Additionally, through the course of our own studies it was discovered that simply abolishing S1P 3 agonism was not sufficient to eliminate the acute and chronic pulmonary toxicity elicited in rodents by 1 or by selective S1P 1 full agonists, findings that led us to discontinue our efforts related to S1P 1 full agonists and seek alternative profiles that could overcome these liabilities. 9 In this letter we describe the identification of a differentiated S1P 1 receptor modulator, BMS-986104 (3d), which distinguishes itself from 1 in terms of cardiovascular and pulmonary safety based on preclinical pharmacology while showing equivalent efficacy in a T-cell transfer colitis model.In our search for S1P 1 agonists that could further dissociate efficacy from toxicity, we evaluated...

The S1P–S1PR Axis in Neurological Disorders—Insights into Current and Future Therapeutic Perspectives

“…Despite similar therapeutic effects, an almost complete absence of adverse events was observed [275]. Similarly, but more recently, BMS-986104 was shown to act equivalently efficient to fingolimod in a T cell transfer colitis model, although not conveying as many cardiovascular and pulmonary adverse events in in vitro settings [276]. Moreover, cenerimod (ACT-334441) could also be confirmed as a potent and selective S1P 1 agonistic signaling properties, whilst broncho-and vasoconstrictive effects were not clinically relevant [277].…”

S1P1 Modulator-Induced Gαi Signaling and β-Arrestin Recruitment Are Both Necessary to Induce Rapid and Efficient Reduction of Blood Lymphocyte Count In Vivo

“…Interestingly, cAMP signaling, b-arrestin recruitment, and S1P 1 receptor internalization were all found to be good predictors of in vivo lymphopenia, but inhibition of cAMP accumulation, which is caused by G ai protein signaling, clearly showed the highest correlation (Xu et al, 2013). Similarly, BMS-986104, a S1P 1 receptor modulator that is potent and fully efficacious in G ai protein signaling, but which induces only partial receptor internalization, was recently reported to be fully efficacious in inhibiting lymphocyte egress in mice (Dhar et al, 2016).…”

“…This hypothesis is supported by the fact that S1P 1 antagonists are also able to induce lymphopenia in vivo (Tarrasón et al, 2011;Quancard et al, 2012). However, it was recently reported that the synthetic agonist BMS-986104 was able to induce lymphopenia without showing complete internalization of S1P 1 receptors (Dhar et al, 2016) and a transgenic mouse, expressing internalization-defective S1P 1 receptors, still showed FTY720-induced lymphopenia, albeit with delayed kinetics (Thangada et al, 2010). Previous reports had suggested S1P 1 agonism to be a mechanism responsible for lymphocyte egress inhibition induced by synthetic agonists All experiments were conducted at the research facilities of Actelion Pharmaceuticals Ltd.…”

Large‐scale chiral supercritical fluid chromatography of a key intermediate in the synthesis of two S1P1 final active pharmaceutical ingredients

“…S1P 1 (sphingosine‐1‐phosphate‐subtype 1) receptor has emerged as an attractive drug target in treatment of autoimmune diseases in recent years . Series of tricyclic , isoxazole , bicyclic , ethanolamine‐based S1P 1 receptor agonists were developed as novel S1P 1 modulators in which the chirality of each individual enantiomer had a significant impact on biological activity, metabolism and toxicity. Thus, preparation of optically pure enantiomers from these compounds became an essential requirement, and SFC played an important role in the program's progression by successfully providing a small amount of structurally diverse S1P 1 APIs.…”