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

  • ACS Med Chem Lett. 2016 Jan 19;7(3):283-8. doi: 10.1021/acsmedchemlett.5b00448.
T G Murali Dhar  1 ,  Hai-Yun Xiao  1 ,  Jenny Xie  1 ,  Lois D Lehman-McKeeman  1 ,  Dauh-Rurng Wu  1 ,  Marta Dabros  1 ,  Xiaoxia Yang  1 ,  Tracy L Taylor  1 ,  Xia D Zhou  1 ,  Elizabeth M Heimrich  1 ,  Rochelle Thomas  1 ,  Kim W McIntyre  1 ,  Bethanne Warrack  1 ,  Hong Shi  1 ,  Paul C Levesque  1 ,  Jia L Zhu  1 ,  James Hennan  1 ,  Praveen Balimane  1 ,  Zheng Yang  1 ,  Anthony M Marino  1 ,  Georgia Cornelius  1 ,  Celia J D'Arienzo  1 ,  Arvind Mathur  1 ,  Ding Ren Shen  1 ,  Mary Ellen Cvijic  1 ,  Luisa Salter-Cid  1 ,  Joel C Barrish  1 ,  Percy H Carter  1 ,  Alaric J Dyckman  1
Affiliations
  • 1. Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
PMID: 26985316 DOI: 10.1021/acsmedchemlett.5b00448
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 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.

Keywords
GPCR; S1P1; S1P3; biased signaling.
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