Identification and Preclinical Pharmacology of BMS-986104: A Differentiated S1P1 Receptor Modulator in Clinical Trials
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- 作者：T. G. Murali Dhar ; Hai-Yun Xiao ; Jenny Xie ; Lois D. Lehman-McKeeman ; Dauh-Rurng Wu ; Marta Dabros ; Xiaoxia Yang ; Tracy L. Taylor ; Xia D. Zhou ; Elizabeth M. Heimrich ; Rochelle Thomas ; Kim W. McIntyre ; Bethanne Warrack ; Hong Shi ; Paul C. Levesque ; Jia L. Zhu ; James Hennan ; Praveen Balimane ; Zheng Yang ; Anthony M. Marino ; Georgia Cornelius ; Celia J. D’Arienzo ; Arvind Mathur ; Ding Ren Shen ; Mary Ellen Cvijic ; Luisa Salter-Cid ; Joel C. Barrish ; Percy H. Carter ; Alaric J. Dyckman
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2016
- 出版时间：March 10, 2016
- 年：2016
- 卷：7
- 期：3
- 页码：283-288
- 全文大小：304K
- ISSN：1948-5875
文摘
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.