title: Design and synthesis of conformationally constrained 3-(N-alkylamino)propylphosphonic acids as potent agonists of sphingosine-1-phosphate (S1P) receptors.
abstract: A series of conformationally constrained 3-(N-alkylamino)propylphosphonic acids were systematically synthesized and their activities as S1P receptor agonists were evaluated. Several pyrrolidine and cyclohexane analogs had S1P receptor profiles comparable to the acyclic lead compound, 3-(N-tetradecylamino)propylphosphonic acid (3), lowered circulating lymphocytes in mice after iv administration and were thus identified as being suitable for further investigations.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. lin_yan@merck.com
authors.forename: Lin
authors.initials: L
authors.lastname: Yan
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Hale
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Lynch
authors.forename: Richard
authors.initials: R
authors.lastname: Budhu
authors.forename: Amy
authors.initials: A
authors.lastname: Gentry
authors.forename: Sander G
authors.initials: SG
authors.lastname: Mills
authors.forename: Richard
authors.initials: R
authors.lastname: Hajdu
authors.forename: Carol Ann
authors.initials: CA
authors.lastname: Keohane
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Rosenbach
authors.forename: James A
authors.initials: JA
authors.lastname: Milligan
authors.forename: Gan-Ju
authors.initials: GJ
authors.lastname: Shei
authors.forename: Gary
authors.initials: G
authors.lastname: Chrebet
authors.forename: James
authors.initials: J
authors.lastname: Bergstrom
authors.forename: Deborah
authors.initials: D
authors.lastname: Card
authors.forename: Hugh
authors.initials: H
authors.lastname: Rosen
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Mandala
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D015195:Drug Design; D006801:Humans; D008968:Molecular Conformation; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D049349:Receptors, Lysosphingolipid / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D063065:Organophosphonates; D049349:Receptors, Lysosphingolipid