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ACS Med Chem Lett. 2016 Jan 19;7(3):283-8. doi: 10.1021/acsmedchemlett.5b00448. eCollection 2016 Mar 10.

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

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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

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