title: Identification of Tricyclic Agonists of Sphingosine-1-phosphate Receptor 1 (S1P1) Employing Ligand-Based Drug Design.
abstract: Fingolimod (1) is the first approved oral therapy for the treatment of relapsing remitting multiple sclerosis. While the phosphorylated metabolite of fingolimod was found to be a nonselective S1P receptor agonist, agonism specifically of S1P1is responsible for the peripheral blood lymphopenia believed to be key to its efficacy. Identification of modulators that maintain activity on S1P1while sparing activity on other S1P receptors could offer equivalent efficacy with reduced liabilities. We disclose in this paper a ligand-based drug design approach that led to the discovery of a series of potent tricyclic agonists of S1P1with selectivity over S1P3and were efficacious in a pharmacodynamic model of suppression of circulating lymphocytes. Compound 10 had the desired pharmacokinetic (PK) and pharmacodynamic (PD) profile and demonstrated maximal efficacy when administered orally in a rat adjuvant arthritis model.
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
authors.forename: Hai-Yun
authors.initials: HY
authors.lastname: Xiao
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
authors.forename: Scott H
authors.initials: SH
authors.lastname: Watterson
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Langevine
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
authors.forename: Anurag S
authors.initials: AS
authors.lastname: Srivastava
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
authors.forename: Soo S
authors.initials: SS
authors.lastname: Ko
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
authors.forename: Yanlei
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Cherney
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Guo
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
authors.forename: John L
authors.initials: JL
authors.lastname: Gilmore
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
authors.forename: James E
authors.initials: JE
authors.lastname: Sheppeck
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
authors.forename: Dauh-Rurng
authors.initials: DR
authors.lastname: Wu
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.affiliation: BMS Biocon Research Center , Bangalore 560099, India.
authors.forename: Duraisamy
authors.initials: D
authors.lastname: Ramasamy
authors.affiliation: BMS Biocon Research Center , Bangalore 560099, India.
authors.forename: Piramanayagam
authors.initials: P
authors.lastname: Arunachalam
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
authors.forename: Arvind
authors.initials: A
authors.lastname: Mathur
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Taylor
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
authors.forename: David J
authors.initials: DJ
authors.lastname: Shuster
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
authors.forename: Kim W
authors.initials: KW
authors.lastname: McIntyre
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
authors.forename: Ding-Ren
authors.initials: DR
authors.lastname: Shen
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
authors.forename: Melissa
authors.initials: M
authors.lastname: Yarde
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Cvijic
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Marino
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
authors.forename: Praveen V
authors.initials: PV
authors.lastname: Balimane
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
authors.forename: Dana M
authors.initials: DM
authors.lastname: Banas
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
authors.forename: Georgia
authors.initials: G
authors.lastname: Cornelius
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
authors.forename: Celia J
authors.initials: CJ
authors.lastname: D'Arienzo
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
authors.forename: Bethanne M
authors.initials: BM
authors.lastname: Warrack
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
authors.forename: Lois
authors.initials: L
authors.lastname: Lehman-McKeeman
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
authors.forename: Luisa M
authors.initials: LM
authors.lastname: Salter-Cid
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
authors.forename: Jenny
authors.initials: J
authors.lastname: Xie
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
authors.forename: Joel C
authors.initials: JC
authors.lastname: Barrish
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
authors.forename: Percy H
authors.initials: PH
authors.lastname: Carter
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
authors.forename: Alaric J
authors.initials: AJ
authors.lastname: Dyckman
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
authors.forename: T G Murali
authors.initials: TG
authors.lastname: Dhar
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000276:immunology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D000068876:Fingolimod Hydrochloride / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D005620:Freund's Adjuvant / Q000008:administration & dosage; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D008214:Lymphocytes / Q000187:drug effects; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009161:Mycobacterium / Q000187:drug effects; D051381:Rats; D011917:Rats, Inbred Lew; D049349:Receptors, Lysosphingolipid / Q000819:agonists*; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D006575:Heterocyclic Compounds, 3-Ring; D008024:Ligands; D049349:Receptors, Lysosphingolipid; D005620:Freund's Adjuvant; D000068876:Fingolimod Hydrochloride