title: Identification and Preclinical Pharmacology of BMS-986104: A Differentiated S1P1 Receptor Modulator in Clinical Trials.
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.
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: T G Murali
authors.initials: TG
authors.lastname: Dhar
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Hai-Yun
authors.initials: HY
authors.lastname: Xiao
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Jenny
authors.initials: J
authors.lastname: Xie
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Lois D
authors.initials: LD
authors.lastname: Lehman-McKeeman
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Dauh-Rurng
authors.initials: DR
authors.lastname: Wu
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Marta
authors.initials: M
authors.lastname: Dabros
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Yang
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Taylor
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Xia D
authors.initials: XD
authors.lastname: Zhou
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Heimrich
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Rochelle
authors.initials: R
authors.lastname: Thomas
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Kim W
authors.initials: KW
authors.lastname: McIntyre
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Bethanne
authors.initials: B
authors.lastname: Warrack
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Hong
authors.initials: H
authors.lastname: Shi
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Levesque
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Jia L
authors.initials: JL
authors.lastname: Zhu
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: James
authors.initials: J
authors.lastname: Hennan
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Praveen
authors.initials: P
authors.lastname: Balimane
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Marino
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Georgia
authors.initials: G
authors.lastname: Cornelius
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Celia J
authors.initials: CJ
authors.lastname: D'Arienzo
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Arvind
authors.initials: A
authors.lastname: Mathur
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Ding Ren
authors.initials: DR
authors.lastname: Shen
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Cvijic
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Luisa
authors.initials: L
authors.lastname: Salter-Cid
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Joel C
authors.initials: JC
authors.lastname: Barrish
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Percy H
authors.initials: PH
authors.lastname: Carter
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Alaric J
authors.initials: AJ
authors.lastname: Dyckman
keywords: GPCR; S1P1; S1P3; biased signaling