Identification and Preclinical Pharmacology of BMS-986104: A Differentiated S1P1 Receptor Modulator in Clinical Trials
| Autor: | Kim W. McIntyre, Luisa Salter-Cid, Bethanne M. Warrack, Celia D’Arienzo, Lois D. Lehman-McKeeman, Rochelle Thomas, Praveen Balimane, Anthony M. Marino, Joel C. Barrish, Elizabeth M. Heimrich, Ding Ren Shen, Xiaoxia Yang, Xia D. Zhou, Jenny Xie, Hong Shi, T. G. Murali Dhar, James Hennan, Jia L. Zhu, Dauh-Rurng Wu, Marta Dabros, Paul Levesque, Percy H. Carter, Arvind Mathur, Mary Ellen Cvijic, Alaric J. Dyckman, Georgia Cornelius, Zheng Yang, Hai-Yun Xiao, Tracy L. Taylor |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Bradycardia business.industry S1p1 receptor Sphingosine-1-phosphate receptor Multiple sclerosis Organic Chemistry Pharmacology medicine.disease Biochemistry Fingolimod Clinical trial 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Drug Discovery Heart rate medicine medicine.symptom Colitis business 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | ACS Medicinal Chemistry Letters. 7:283-288 |
| ISSN: | 1948-5875 |
| DOI: | 10.1021/acsmedchemlett.5b00448 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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