Identification and Preclinical Pharmacology of ((1R,3S)-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(1)) Modulator Advanced into Clinical Trials

摘要

Recently, our research group reported the identification of BMS-986104 (2) as a differentiated S1P(1) receptor modulator. In comparison to fingolimod (1), a full agonist of S1P(1) 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-1/2) longer than that of 1, as well as a reduced formation of the phosphate metabolite that is required for activity against S1P(1). Herein, we describe our efforts to discover highly potent, partial agonists of S1P(1) with a shorter T-1/2 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.