1区 · 医学
Article
作者: Dabros, Marta ; Mathur, Arvind ; Zhou, Xia D. ; Gilmore, John L. ; Chen, Cliff ; Lehman-McKeeman, Lois D. ; Gong, Lei ; Dyckman, Alaric J. ; Levesque, Paul C. ; Marino, Anthony M. ; Gupta, Anuradha ; Shi, Hong ; Yang, Zheng ; Wu, Dauh-Rurng ; Salter-Cid, Luisa M. ; Xie, Jenny ; McIntyre, Kim W. ; Borowski, Virna ; Sun, Huadong ; Li, Yuwen ; Heimrich, Elizabeth M. ; Taylor, Tracy L. ; Cornelius, Georgia ; Cvijic, Mary Ellen ; Lecureux, Lloyd ; Dhar, T. G. Murali ; Carter, Percy H. ; Xiao, Hai-Yun ; Shen, Ding Ren ; Pragalathan, Bala ; Xiao, Zili ; Yang, Xiaoxia ; Warrack, Bethanne M. ; D’Arienzo, Celia J. ; Rampulla, Richard ; Yang, Michael G. ; Thomas, Rochelle
Recently, our research group reported the identification of BMS-986104 (2) as a differentiated S1P1 receptor modulator. In comparison to fingolimod (1), a full agonist of S1P1 currently marketed for the treatment of relapse remitting multiple sclerosis (RRMS), 2 offers several potential advantages having demonstrated improved safety multiples in preclinical evaluations against undesired pulmonary and cardiovascular effects. In clinical trials, 2 was found to exhibit a pharmacokinetic half-life ( T1/2) longer than that of 1, as well as a reduced formation of the phosphate metabolite that is required for activity against S1P1. Herein, we describe our efforts to discover highly potent, partial agonists of S1P1 with a shorter T1/2 and increased in vivo phosphate metabolite formation. These efforts culminated in the discovery of BMS-986166 (14a), which was advanced to human clinical evaluation. The pharmacokinetic/pharmacodynamic (PK/PD) relationship as well as pulmonary and cardiovascular safety assessments are discussed. Furthermore, efficacy of 14a in multiple preclinical models of autoimmune diseases are presented.
