2016
DOI: 10.1021/acsmedchemlett.5b00448
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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 pulmona… Show more

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Cited by 25 publications
(33 citation statements)
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“…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].…”
Section: Insights Into Current and Future Therapeutic Perspectivesmentioning
confidence: 91%
“…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].…”
Section: Insights Into Current and Future Therapeutic Perspectivesmentioning
confidence: 91%
“…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).…”
Section: Discussionmentioning
confidence: 96%
“…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.…”
Section: Introductionmentioning
confidence: 88%
“…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.…”
Section: Introductionmentioning
confidence: 99%