title: Identification and synthesis of potent and selective pyridyl-isoxazole based agonists of sphingosine-1-phosphate 1 (S1P1).
abstract: The synthesis and structure-activity relationship (SAR) of a series of pyridyl-isoxazole based agonists of S1P1 are discussed. Compound 5b provided potent in vitro activity with selectivity, had an acceptable pharmacokinetic profile, and demonstrated efficacy in a dose dependent manner when administered orally in a rodent model of arthritis.
authors.affiliation: Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-4000, United States. Electronic address: junqing.guo@bms.com.
authors.forename: Junqing
authors.initials: J
authors.lastname: Guo
authors.affiliation: Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-4000, United States.
authors.forename: Scott H
authors.initials: SH
authors.lastname: Watterson
authors.affiliation: Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-4000, United States.
authors.forename: Steven H
authors.initials: SH
authors.lastname: Spergel
authors.affiliation: Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-4000, United States.
authors.forename: James
authors.initials: J
authors.lastname: Kempson
authors.affiliation: Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-4000, United States.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Langevine
authors.affiliation: Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-4000, United States.
authors.forename: Ding Ren
authors.initials: DR
authors.lastname: Shen
authors.affiliation: Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-4000, United States.
authors.forename: Melissa
authors.initials: M
authors.lastname: Yarde
authors.affiliation: Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-4000, United States.
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Cvijic
authors.affiliation: Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-4000, United States.
authors.forename: Dana
authors.initials: D
authors.lastname: Banas
authors.affiliation: Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-4000, United States.
authors.forename: Richard
authors.initials: R
authors.lastname: Liu
authors.affiliation: Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-4000, United States.
authors.forename: Suzanne J
authors.initials: SJ
authors.lastname: Suchard
authors.affiliation: Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-4000, United States.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Gillooly
authors.affiliation: Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-4000, United States.
authors.forename: Tracy
authors.initials: T
authors.lastname: Taylor
authors.affiliation: Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-4000, United States.
authors.forename: Sandra
authors.initials: S
authors.lastname: Rex-Rabe
authors.affiliation: Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-4000, United States.
authors.forename: David J
authors.initials: DJ
authors.lastname: Shuster
authors.affiliation: Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-4000, United States.
authors.forename: Kim W
authors.initials: KW
authors.lastname: McIntyre
authors.affiliation: Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-4000, United States.
authors.forename: Georgia
authors.initials: G
authors.lastname: Cornelius
authors.affiliation: Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-4000, United States.
authors.forename: Celia
authors.initials: C
authors.lastname: D'Arienzo
authors.affiliation: Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-4000, United States.
authors.forename: Anthony
authors.initials: A
authors.lastname: Marino
authors.affiliation: Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-4000, United States.
authors.forename: Praveen
authors.initials: P
authors.lastname: Balimane
authors.affiliation: Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-4000, United States.
authors.forename: Luisa
authors.initials: L
authors.lastname: Salter-Cid
authors.affiliation: Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-4000, United States.
authors.forename: Murray
authors.initials: M
authors.lastname: McKinnon
authors.affiliation: Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-4000, United States.
authors.forename: Joel C
authors.initials: JC
authors.lastname: Barrish
authors.affiliation: Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-4000, United States.
authors.forename: Percy H
authors.initials: PH
authors.lastname: Carter
authors.affiliation: Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-4000, United States.
authors.forename: William J
authors.initials: WJ
authors.lastname: Pitts
authors.affiliation: Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-4000, United States.
authors.forename: Jenny
authors.initials: J
authors.lastname: Xie
authors.affiliation: Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-4000, United States.
authors.forename: Alaric J
authors.initials: AJ
authors.lastname: Dyckman
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy*; D060326:Chemistry Techniques, Synthetic; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry / Q000494:pharmacology; D018655:Lymphocyte Count; D008246:Lysophospholipids / Q000819:agonists*; D008297:Male; D011917:Rats, Inbred Lew; D049349:Receptors, Lysosphingolipid / Q000819:agonists; D013110:Sphingosine / Q000819:agonists / Q000031:analogs & derivatives*; D013329:Structure-Activity Relationship
chemical_list: D007555:Isoxazoles; D008246:Lysophospholipids; D049349:Receptors, Lysosphingolipid; C060506:sphingosine 1-phosphate; D013110:Sphingosine
keywords: FTY720; Fingolimod; Isoxazole; S1P(1); Sphingosine-1-phosphate; Sphingosine-1-phosphate 1