title: Identification of benzoxazole analogs as novel, S1P(3) sparing S1P(1) agonists.
abstract: A novel series of benzoxazole-derived S1P(1) agonists were designed based on scaffold hopping molecular design strategy combined with computational approaches. Extensive SAR studies led to the discovery of compound 17d as a selective S1P(1) agonist (over S1P(3)) with high CNS penetration and favorable DMPK properties. 17d also demonstrated in vivo pharmacological efficacy to reduce blood lymphocyte in mice after oral administration.
authors.affiliation: Research and Development, GlaxoSmithKline Pharmaceuticals, 898 Halei Road, Zhangjiang Hi-tech Park, Pudong, Shanghai 201023, China.
authors.forename: Guanghui
authors.initials: G
authors.lastname: Deng
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Meng
authors.forename: Qian
authors.initials: Q
authors.lastname: Liu
authors.forename: Xuesong
authors.initials: X
authors.lastname: Xu
authors.forename: Qiongfeng
authors.initials: Q
authors.lastname: Xu
authors.forename: Feng
authors.initials: F
authors.lastname: Ren
authors.forename: Taylor B
authors.initials: TB
authors.lastname: Guo
authors.forename: Hongtao
authors.initials: H
authors.lastname: Lu
authors.forename: Jia-Ning
authors.initials: JN
authors.lastname: Xiang
authors.forename: John D
authors.initials: JD
authors.lastname: Elliott
authors.forename: Xichen
authors.initials: X
authors.lastname: Lin
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001583:Benzoxazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D018655:Lymphocyte Count; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects*; D051379:Mice; D008958:Models, Molecular; D011485:Protein Binding; D049349:Receptors, Lysosphingolipid / Q000819:agonists* / Q000378:metabolism; D012680:Sensitivity and Specificity; D000081025:Sphingosine-1-Phosphate Receptors; D013329:Structure-Activity Relationship
chemical_list: D001583:Benzoxazoles; D007166:Immunosuppressive Agents; D049349:Receptors, Lysosphingolipid; C501285:S1pr3 protein, mouse; D000081025:Sphingosine-1-Phosphate Receptors; D002118:Calcium