title: Discovery of 3-arylpropionic acids as potent agonists of sphingosine-1-phosphate receptor-1 (S1P1) with high selectivity against all other known S1P receptor subtypes.
abstract: A series of 3-arylpropionic acids were synthesized as S1P1 receptor agonists. Structure-activity relationship studies on the pendant phenyl ring revealed several structural features offering selectivity of S1P1 binding against S1P2-5. These highly selective S1P1 agonists induced peripheral blood lymphocyte lowering in mice and one of them was found to be efficacious in a rat skin transplantation model, supporting that S1P1 agonism is primarily responsible for the immunosuppressive efficacy observed in preclinical animal models.
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: Pei
authors.initials: P
authors.lastname: Huo
authors.forename: George
authors.initials: G
authors.lastname: Doherty
authors.forename: Lesile
authors.initials: L
authors.lastname: Toth
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Hale
authors.forename: Sander G
authors.initials: SG
authors.lastname: Mills
authors.forename: Richard
authors.initials: R
authors.lastname: Hajdu
authors.forename: Carol A
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: Elizabeth
authors.initials: E
authors.lastname: Quackenbush
authors.forename: Alexandra
authors.initials: A
authors.lastname: Wickham
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Mandala
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008024:Ligands; D018655:Lymphocyte Count / Q000662:veterinary; D051379:Mice; D010666:Phenylpropionates / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D049349:Receptors, Lysosphingolipid / Q000819:agonists*; D016038:Skin Transplantation; D013329:Structure-Activity Relationship
chemical_list: D007166:Immunosuppressive Agents; D008024:Ligands; D010666:Phenylpropionates; D049349:Receptors, Lysosphingolipid