1. Academic Validation
  2. 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.
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.

Figures
Products