title: ASP4058, a novel agonist for sphingosine 1-phosphate receptors 1 and 5, ameliorates rodent experimental autoimmune encephalomyelitis with a favorable safety profile.
abstract: Sphingosine-1-phosphate (S1P) is a biologically active sphingolipid that acts through the members of a family of five G protein-coupled receptors (S1P1-S1P5). S1P1 is a major regulator of lymphocyte trafficking, and fingolimod, whose active metabolite fingolimod phosphate acts as a nonselective S1P receptor agonist, exerts its immunomodulatory effect, at least in part, by regulating the lymphocyte trafficking by inducing down regulation of lymphocyte S1P1. Here, we detail the pharmacological profile of 5-{5-[3-(trifluoromethyl)-4-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl]-1,2,4-oxadiazol-3-yl}-1H-benzimidazole (ASP4058), a novel next-generation S1P receptor agonist selective for S1P1 and S1P5. ASP4058 preferentially activates S1P1 and S1P5 compared with S1P2, 3, 4 in GTPγS binding assays in vitro. Oral administration of ASP4058 reduced the number of peripheral lymphocytes and inhibited the development of experimental autoimmune encephalomyelitis (EAE) in Lewis rats. Further, ASP4058 prevented relapse of disease in a mouse model of relapsing-remitting EAE. Although these immunomodulatory effects were comparable to those of fingolimod, ASP4058 showed a wider safety margin than fingolimod for bradycardia and bronchoconstriction in rodents. These observations suggest that ASP4058 represents a new therapeutic option for treating multiple sclerosis that is safer than nonselective S1P receptor agonists such as fingolimod.
authors.affiliation: Tsukuba Research Center, Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Yamamoto
authors.affiliation: Tsukuba Research Center, Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan.
authors.forename: Youhei
authors.initials: Y
authors.lastname: Okada
authors.affiliation: Tsukuba Research Center, Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Hirose
authors.affiliation: Tsukuba Research Center, Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan.
authors.forename: Tadatsura
authors.initials: T
authors.lastname: Koshika
authors.affiliation: Tsukuba Research Center, Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Kawato
authors.affiliation: Tsukuba Research Center, Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Maeda
authors.affiliation: Kashima R&D Center, Drug Discovery Research, Astellas Pharma Inc., Osaka, Japan.
authors.forename: Rika
authors.initials: R
authors.lastname: Saito
authors.affiliation: Tsukuba Research Center, Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Hattori
authors.affiliation: Tsukuba Research Center, Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Harada
authors.affiliation: Tsukuba Research Center, Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan.
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Nagasaka
authors.affiliation: Tsukuba Research Center, Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan.
authors.forename: Tatsuaki
authors.initials: T
authors.lastname: Morokata
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D016084:Bronchoconstriction / Q000187:drug effects; D002460:Cell Line; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000517:prevention & control; D005260:Female; D000068876:Fingolimod Hydrochloride; D006339:Heart Rate / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D010069:Oxadiazoles / Q000494:pharmacology*; D011409:Propylene Glycols / Q000494:pharmacology; D051381:Rats; D049349:Receptors, Lysosphingolipid / Q000819:agonists* / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C000598902:ASP4058; D001562:Benzimidazoles; D010069:Oxadiazoles; D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine