title: Structure-activity relationship studies of S1P agonists with a dihydronaphthalene scaffold.
abstract: Structure-activity relationship (SAR) of sphingosine-1-phosphate receptor agonists with a dihydronaphthalene scaffold was investigated. Compound 1 was modified to improve S1P(1) agonistic activity and in vivo peripheral lymphocyte lowering (PLL) activity without impairing selectivity over S1P(3) agonistic activity. A detailed SAR study of the terminal lipophilic part revealed that the introduction of substituents on the propylene linker and the terminal benzene ring influences in vitro and PLL activities. Compound 6n bearing a (S)-methyl group at the 2-position on the propylene linker and chlorine at the para-position on the terminal benzene ring showed potent hS1P(1) agonistic activity with excellent selectivity over hS1P(3) and in vivo PLL activity in mice.
authors.affiliation: Medicinal Chemistry Research Laboratories, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan. h.kurata@ono.co.jp
authors.forename: Haruto
authors.initials: H
authors.lastname: Kurata
authors.forename: Kensuke
authors.initials: K
authors.lastname: Kusumi
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Otsuki
authors.forename: Ryo
authors.initials: R
authors.lastname: Suzuki
authors.forename: Masakuni
authors.initials: M
authors.lastname: Kurono
authors.forename: Natsuko
authors.initials: N
authors.lastname: Tokuda
authors.forename: Yuka
authors.initials: Y
authors.lastname: Takada
authors.forename: Hiroki
authors.initials: H
authors.lastname: Shioya
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Mizuno
authors.forename: Takaki
authors.initials: T
authors.lastname: Komiya
authors.forename: Takeji
authors.initials: T
authors.lastname: Ono
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hagiya
authors.forename: Masashi
authors.initials: M
authors.lastname: Minami
authors.forename: Shinji
authors.initials: S
authors.lastname: Nakade
authors.forename: Hiromu
authors.initials: H
authors.lastname: Habashita
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001554:Benzene / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D002713:Chlorine / Q000737:chemistry; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008246:Lysophospholipids / Q000037:antagonists & inhibitors*; D051379:Mice; D008956:Models, Chemical; D009281:Naphthalenes / Q000737:chemistry*; D051381:Rats; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D008246:Lysophospholipids; D009281:Naphthalenes; D049349:Receptors, Lysosphingolipid; C031721:naphthalene; C060506:sphingosine 1-phosphate; D002713:Chlorine; D001554:Benzene; D013110:Sphingosine