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 (S1P₁) Modulator Advanced into Clinical Trials

Abstract

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.

The safety and pharmacokinetics of a novel, selective S1P1R modulator in healthy participants

“…However, compounds with an increased selectivity for S1P1R have not shown improved cardiovascular safety profiles in humans, indicating that, relative to to certain other species, bradycardia in humans is more dependent on S1P1R activity [14]. In S1P1R/CHO cells, BMS-986166 has demonstrated partial agonism in S1P1R internalization assays and weaker potency in S1P1R ERK phosphorylation assays versus previous compounds; BMT-121795 has been shown to behave similarly to fingolimod phosphate in S1P1R binding and cAMP assays [16]. In human cardiomyocyte beating rate assays, BMT-121795 showed weaker potency compared with fingolimod phosphate, indicating that the unique S1P1R-biased agonism of BMT-121795 may contribute to its reduced potency in human cardiomyocyte assay and reduced risk of HR decrease in humans [16].…”

“…The dose selection for the MAD study was based on a proposed PK/PD model for the inhibition of lymphocyte trafficking into the circulation developed from preclinical models [16] and the PK and PD data obtained from the SAD study.…”

“…BMS-986166 is a selective S1P receptor modulator with a higher specificity for S1P1R than for other S1P receptors, especially S1P3R, and therefore has higher clinical potential for the treatment of autoimmune diseases [15]. BMS-986166 efficiently reduced blood lymphocyte counts in rats and showed excellent pharmacokinetic (PK) properties across species [16]. The weaker potency of BMS-986166 versus other S1P1R agonists in human-induced pluripotent stem cell-derived cardiomyocyte beating rate assays [16] are indicative preclinically of a lower risk of cardiovascular and macular edema in humans than that associated with fingolimod [15].…”

“…BMS-986166 efficiently reduced blood lymphocyte counts in rats and showed excellent pharmacokinetic (PK) properties across species [16]. The weaker potency of BMS-986166 versus other S1P1R agonists in human-induced pluripotent stem cell-derived cardiomyocyte beating rate assays [16] are indicative preclinically of a lower risk of cardiovascular and macular edema in humans than that associated with fingolimod [15]. Like fingolimod, BMS-986166 is phosphorylated in vivo to its pharmacologically active form (BMS-986166-P, referred to as BMT-121795).…”

Population Pharmacokinetic Analysis of BMS‐986166, a Novel Selective Sphingosine‐1‐Phosphate‐1 Receptor Modulator, and Exposure‐Response Assessment of Lymphocyte Counts and Heart Rate in Healthy Participants

“…Sphingosine‐1‐phosphate (S1P) is a bioactive lysophospholipid that mediates a variety of cellular responses by the stimulation of the G‐protein–coupled S1P receptors (S1PRs) 1,2,3,4,5 (S1P1‐5R) 1,2 present on a wide range of human cells and tissues. The sphingosine‐1‐phosphate‐1 receptor (S1P1R) subtype is expressed on the surface of lymphocytes and is important in regulating egress of T cells and B cells from peripheral lymph nodes 3 .…”