title: 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: ONO-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 (EC(50) ) 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.
authors.affiliation: Exploratory Research Laboratories, Tsukuba, Ibaraki, Japan. t.komiya@ono.co.jp
authors.forename: T
authors.initials: T
authors.lastname: Komiya
authors.forename: K
authors.initials: K
authors.lastname: Sato
authors.forename: H
authors.initials: H
authors.lastname: Shioya
authors.forename: Y
authors.initials: Y
authors.lastname: Inagaki
authors.forename: H
authors.initials: H
authors.lastname: Hagiya
authors.forename: R
authors.initials: R
authors.lastname: Kozaki
authors.forename: M
authors.initials: M
authors.lastname: Imai
authors.forename: Y
authors.initials: Y
authors.lastname: Takada
authors.forename: T
authors.initials: T
authors.lastname: Maeda
authors.forename: H
authors.initials: H
authors.lastname: Kurata
authors.forename: M
authors.initials: M
authors.lastname: Kurono
authors.forename: R
authors.initials: R
authors.lastname: Suzuki
authors.forename: K
authors.initials: K
authors.lastname: Otsuki
authors.forename: H
authors.initials: H
authors.lastname: Habashita
authors.forename: S
authors.initials: S
authors.lastname: Nakade
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy*; D005260:Female; D007155:Immunologic Factors / Q000627:therapeutic use*; D018655:Lymphocyte Count; D008214:Lymphocytes / Q000187:drug effects; D051379:Mice; D016688:Mice, Inbred NOD; D009103:Multiple Sclerosis / Q000188:drug therapy*; D051381:Rats; D011917:Rats, Inbred Lew; D049349:Receptors, Lysosphingolipid / Q000819:agonists*; D013116:Spinal Cord / Q000187:drug effects
chemical_list: D007155:Immunologic Factors; D049349:Receptors, Lysosphingolipid