title: Discovery of potent 3,5-diphenyl-1,2,4-oxadiazole sphingosine-1-phosphate-1 (S1P1) receptor agonists with exceptional selectivity against S1P2 and S1P3.
abstract: A class of 3,5-diphenyl-1,2,4-oxadiazole based compounds have been identified as potent sphingosine-1-phosphate-1 (S1P1) receptor agonists with minimal affinity for the S1P2 and S1P3 receptor subtypes. Analogue 26 (S1P1 IC50 = 0.6 nM) has an excellent pharmacokinetics profile in the rat and dog and is efficacious in a rat skin transplant model, indicating that S1P3 receptor agonism is not a component of immunosuppressive efficacy.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratory, Rahway, New Jersey 07065, USA. zhen_li@merck.com
authors.forename: Zhen
authors.initials: Z
authors.lastname: Li
authors.forename: Weirong
authors.initials: W
authors.lastname: Chen
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Hale
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Lynch
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: Stephen A
authors.initials: SA
authors.lastname: Parent
authors.forename: James
authors.initials: J
authors.lastname: Bergstrom
authors.forename: Deborah
authors.initials: D
authors.lastname: Card
authors.forename: Michael
authors.initials: M
authors.lastname: Forrest
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Quackenbush
authors.forename: L Alexandra
authors.initials: LA
authors.lastname: Wickham
authors.forename: Hugo
authors.initials: H
authors.lastname: Vargas
authors.forename: Rose M
authors.initials: RM
authors.lastname: Evans
authors.forename: Hugh
authors.initials: H
authors.lastname: Rosen
authors.forename: Suzanne
authors.initials: S
authors.lastname: Mandala
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D006085:Graft Survival; D007166:Immunosuppressive Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D018655:Lymphocyte Count; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D049349:Receptors, Lysosphingolipid / Q000819:agonists*; D016038:Skin Transplantation; D013329:Structure-Activity Relationship
chemical_list: D007166:Immunosuppressive Agents; D010069:Oxadiazoles; D049349:Receptors, Lysosphingolipid