2. Academic Validation
  3. Identification and Preclinical Pharmacology of BMS-986104: A Differentiated S1P1 Receptor Modulator in Clinical Trials

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

Affiliation

  • 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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