title: Potent and Selective Agonists of Sphingosine 1-Phosphate 1 (S1P1): Discovery and SAR of a Novel Isoxazole Based Series.
abstract: Sphingosine 1-phosphate (S1P) is the endogenous ligand for the sphingosine 1-phosphate receptors (S1P1-5) and evokes a variety of cellular responses through their stimulation. The interaction of S1P with the S1P receptors plays a fundamental physiological role in a number of processes including vascular development and stabilization, lymphocyte migration, and proliferation. Agonism of S1P1, in particular, has been shown to play a significant role in lymphocyte trafficking from the thymus and secondary lymphoid organs, resulting in immunosuppression. This article will detail the discovery and SAR of a potent and selective series of isoxazole based full agonists of S1P1. Isoxazole 6d demonstrated impressive efficacy when administered orally in a rat model of arthritis and in a mouse experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis.
authors.affiliation: Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton, New Jersey 08543, United States.
authors.forename: Scott H
authors.initials: SH
authors.lastname: Watterson
authors.affiliation: Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton, New Jersey 08543, United States.
authors.forename: Junqing
authors.initials: J
authors.lastname: Guo
authors.affiliation: Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton, New Jersey 08543, United States.
authors.forename: Steve H
authors.initials: SH
authors.lastname: Spergel
authors.affiliation: Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton, New Jersey 08543, United States.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Langevine
authors.affiliation: Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton, New Jersey 08543, United States.
authors.forename: Robert V
authors.initials: RV
authors.lastname: Moquin
authors.affiliation: Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton, New Jersey 08543, United States.
authors.forename: Ding Ren
authors.initials: DR
authors.lastname: Shen
authors.affiliation: Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton, New Jersey 08543, United States.
authors.forename: Melissa
authors.initials: M
authors.lastname: Yarde
authors.affiliation: Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton, New Jersey 08543, United States.
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Cvijic
authors.affiliation: Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton, New Jersey 08543, United States.
authors.forename: Dana
authors.initials: D
authors.lastname: Banas
authors.affiliation: Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton, New Jersey 08543, United States.
authors.forename: Richard
authors.initials: R
authors.lastname: Liu
authors.affiliation: Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton, New Jersey 08543, United States.
authors.forename: Suzanne J
authors.initials: SJ
authors.lastname: Suchard
authors.affiliation: Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton, New Jersey 08543, United States.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Gillooly
authors.affiliation: Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton, New Jersey 08543, United States.
authors.forename: Tracy
authors.initials: T
authors.lastname: Taylor
authors.affiliation: Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton, New Jersey 08543, United States.
authors.forename: Sandra
authors.initials: S
authors.lastname: Rex-Rabe
authors.affiliation: Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton, New Jersey 08543, United States.
authors.forename: David J
authors.initials: DJ
authors.lastname: Shuster
authors.affiliation: Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton, New Jersey 08543, United States.
authors.forename: Kim W
authors.initials: KW
authors.lastname: McIntyre
authors.affiliation: Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton, New Jersey 08543, United States.
authors.forename: Georgia
authors.initials: G
authors.lastname: Cornelius
authors.affiliation: Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton, New Jersey 08543, United States.
authors.forename: Celia
authors.initials: C
authors.lastname: D'Arienzo
authors.affiliation: Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton, New Jersey 08543, United States.
authors.forename: Anthony
authors.initials: A
authors.lastname: Marino
authors.affiliation: Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton, New Jersey 08543, United States.
authors.forename: Praveen
authors.initials: P
authors.lastname: Balimane
authors.affiliation: Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton, New Jersey 08543, United States.
authors.forename: Bethanne
authors.initials: B
authors.lastname: Warrack
authors.affiliation: Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton, New Jersey 08543, United States.
authors.forename: Luisa
authors.initials: L
authors.lastname: Salter-Cid
authors.affiliation: Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton, New Jersey 08543, United States.
authors.forename: Murray
authors.initials: M
authors.lastname: McKinnon
authors.affiliation: Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton, New Jersey 08543, United States.
authors.forename: Joel C
authors.initials: JC
authors.lastname: Barrish
authors.affiliation: Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton, New Jersey 08543, United States.
authors.forename: Percy H
authors.initials: PH
authors.lastname: Carter
authors.affiliation: Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton, New Jersey 08543, United States.
authors.forename: William J
authors.initials: WJ
authors.lastname: Pitts
authors.affiliation: Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton, New Jersey 08543, United States.
authors.forename: Jenny
authors.initials: J
authors.lastname: Xie
authors.affiliation: Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton, New Jersey 08543, United States.
authors.forename: Alaric J
authors.initials: AJ
authors.lastname: Dyckman
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy; D016466:CHO Cells; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D055808:Drug Discovery; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy; D006801:Humans; D007166:Immunosuppressive Agents / Q000138:chemical synthesis / Q000494:pharmacology; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D008208:Lymphatic System / Q000166:cytology / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects; D008246:Lysophospholipids / Q000819:agonists*; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D011917:Rats, Inbred Lew; D013110:Sphingosine / Q000819:agonists / Q000031:analogs & derivatives*; D013329:Structure-Activity Relationship; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects
chemical_list: D007166:Immunosuppressive Agents; D007555:Isoxazoles; D008246:Lysophospholipids; C060506:sphingosine 1-phosphate; D013110:Sphingosine