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

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 d...

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Published in:ACS medicinal chemistry letters 2016-03, Vol.7 (3), p.283-288
Main Authors: Dhar, T. G. Murali, Xiao, Hai-Yun, Xie, Jenny, Lehman-McKeeman, Lois D, Wu, Dauh-Rurng, Dabros, Marta, Yang, Xiaoxia, Taylor, Tracy L, Zhou, Xia D, Heimrich, Elizabeth M, Thomas, Rochelle, McIntyre, Kim W, Warrack, Bethanne, Shi, Hong, Levesque, Paul C, Zhu, Jia L, Hennan, James, Balimane, Praveen, Yang, Zheng, Marino, Anthony M, Cornelius, Georgia, D’Arienzo, Celia J, Mathur, Arvind, Shen, Ding Ren, Cvijic, Mary Ellen, Salter-Cid, Luisa, Barrish, Joel C, Carter, Percy H, Dyckman, Alaric J
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Language:English
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Summary: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 S1P1 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.
ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.5b00448