title: A rational utilization of high-throughput screening affords selective, orally bioavailable 1-benzyl-3-carboxyazetidine sphingosine-1-phosphate-1 receptor agonists.
abstract: Moderately potent, selective S1P(1) receptor agonists identified from high-throughput screening have been adapted into lipophilic tails for a class of orally bioavailable amino acid-based S1P(1) agonists represented by 7. Many of the new compounds are potent S1P(1) agonists that select against the S1P(2), S1P(3), and S1P(4) (although not S1P(5)) receptor subtypes. Analogues 18 and 24 are highly orally bioavailable and possess excellent pharmacokinetic profiles in the rat, dog, and rhesus monkey.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, New Jersey 07065, USA. jeffrey_hale@merck.com
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Hale
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Lynch
authors.forename: William
authors.initials: W
authors.lastname: Neway
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: Stephen A
authors.initials: SA
authors.lastname: Parent
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: Marc
authors.initials: M
authors.lastname: Ferrer
authors.forename: Peter
authors.initials: P
authors.lastname: Hodder
authors.forename: Berta
authors.initials: B
authors.lastname: Strulovici
authors.forename: Hugh
authors.initials: H
authors.lastname: Rosen
authors.forename: Suzanne
authors.initials: S
authors.lastname: Mandala
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001384:Azetidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D016466:CHO Cells; D006224:Cricetinae; D004285:Dogs; D015195:Drug Design; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D008214:Lymphocytes / Q000187:drug effects; D008253:Macaca mulatta; D051379:Mice; D051381:Rats; D011917:Rats, Inbred Lew; D049349:Receptors, Lysosphingolipid / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D001384:Azetidines; D007166:Immunosuppressive Agents; D049349:Receptors, Lysosphingolipid; D016244:Guanosine 5'-O-(3-Thiotriphosphate)