Identification and Preclinical Pharmacology of ((1 R,3 S)-1-Amino-3-(( S)-6-(2-methoxyphenethyl)-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopentyl)methanol (BMS-986166): A Differentiated Sphingosine-1-phosphate Receptor 1 (S1P) Modulator Advanced into Clinical Trials.
Gilmore JL,Xiao HY,Dhar TGM,Yang MG,Xiao Z,Xie J,Lehman-McKeeman LD,Gong L,Sun H,Lecureux L,Chen C,Wu DR,Dabros M,Yang X,Taylor TL,Zhou XD,Heimrich EM,Thomas R,McIntyre KW,Borowski V,Warrack BM,Li Y,Shi H,Levesque PC,Yang Z,Marino AM,Cornelius G,D'Arienzo CJ,Mathur A,Rampulla R,Gupta A,Pragalathan B,Shen DR,Cvijic ME,Salter-Cid LM,Carter PH,Dyckman AJ
Recently, our research group reported the identification of BMS-986104 (2) as a differentiated S1P receptor modulator. In comparison to fingolimod (1), a full agonist of S1P 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 ( T) longer than that of 1, as well as a reduced formation of the phosphate metabolite that is required for activity against S1P. Herein, we describe our efforts to discover highly potent, partial agonists of S1P with a shorter T 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.