Efficacy and immunomodulatory actions of ONO-4641, a novel selective agonist for sphingosine 1-phosphate receptors 1 and 5, in preclinical models of multiple sclerosis

Abstract

SummaryONO-4641 is a next-generation sphingosine 1-phosphate (S1P) receptor agonist selective for S1P receptors 1 and 5. The objective of the study was to characterize the immunomodulatory effects of ONO-4641 using preclinical data. ONO-4641 was tested in both in-vitro pharmacological studies as well as in-vivo models of transient or relapsing-remitting experimental autoimmune encephalomyelitis (EAE). In vitro, ONO-4641 showed highly potent agonistic activities versus S1P receptors 1 and 5 [half maximal effective concentration (EC50) values of 0·0273 and 0·334 nM, respectively], and had profound S1P receptor 1 down-regulating effects on the cell membrane. ONO-4641 decreased peripheral blood lymphocyte counts in rats by inhibiting lymphocyte egress from secondary lymphoid tissues. In a rat experimental autoimmune encephalomyelitis (EAE) model, ONO-4641 suppressed the onset of disease and inhibited lymphocyte infiltration into the spinal cord in a dose-dependent manner at doses of 0·03 and 0·1 mg/kg. Furthermore, ONO-4641 prevented relapse of disease in a non-obese diabetic mouse model of relapsing-remitting EAE. These observations suggest that ONO-4641 may provide therapeutic benefits in the treatment of multiple sclerosis.

Targeting the sphingosine-1-phosphate axis in cancer, inflammation and beyond

“…Other examples of S1PR1-directed drugs include ONO-4641 (REF. 69), which is a novel selective agonist for both S1PR1 and S1PR5, and ponesimod (ACT-128800) 70 , which is a potent selective S1PR1 modulator; both of these drugs have been effective in rodent models and are now in Phase II clinical trials for multiple sclerosis and moderate-to-severe chronic plaque psoriasis, respectively (TABLE 2). Other modulators of S1PRs are being investigated in several preclinical disease models (TABLE 1), including viral responses, cancer treatments and modulation of angiogenesis.…”

Clinical pharmacology, efficacy, and safety aspects of sphingosine-1-phosphate receptor modulators

“…amiselimod, E: ceralifimod, F: ozanimod, and G: siponimod. Figure 3: EC50 values of the non-selective sphingosine-1-phosphate (S1P) receptor modulator (fingolimod phosphate) [114], selective S1P1 receptor modulators (ponesimod [115], amiselimod [10], ceralifimod [116], ozanimod [117], and siponimod [47]), and natural ligand (S1P) for the 5 S1P receptor subtypes. To make the graph readible, values corresponding to 1/EC50 (nM-1) are presented.…”

Design, Synthesis, and In Vitro and In Vivo Evaluation of an 18F-Labeled Sphingosine 1-Phosphate Receptor 1 (S1P1) PET Tracer

“…Although the reason for this discrepancy in the assay results is not clear, similar results have been observed with other S1P receptor ligands. 41 Additionally, while functional assays can be extremely useful in the preliminary stages of imaging agent development, the binding potency of a ligand cannot be determined without a competitive binding assay. 42 While none of the ligands in this series had sufficient binding affinity (IC 50 < 10 nM) to be pursued as a PET tracer, structure–activity relationships (SAR) became apparent.…”