title: SAR studies of 3-arylpropionic acids as potent and selective agonists of sphingosine-1-phosphate receptor-1 (S1P1) with enhanced pharmacokinetic properties.
abstract: Structure-activity relationship (SAR) studies of 3-arylpropionic acids-a class of novel S1P(1) selective agonists-by introducing substitution to the propionic acid chain and replacing the adjacent phenyl ring with pyridine led to a series of modified 3-arylpropionic acids with enhanced half-life in rat. These analogs (e.g., cyclopropanecarboxylic acids) exhibited longer half-life in rat than did unmodified 3-arylpropionic acids. This result suggests that metabolic oxidation at the propionic acid chain, particularly at the C3 benzylic position of 3-arylpropionic acids, is probably responsible for their short half-life in rodent.
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: 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: Suzanne M
authors.initials: SM
authors.lastname: Mandala
mesh_terms: D000818:Animals; D001682:Biological Availability; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006207:Half-Life; D018655:Lymphocyte Count; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D011422:Propionates / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D049349:Receptors, Lysosphingolipid / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D011422:Propionates; D049349:Receptors, Lysosphingolipid; D016244:Guanosine 5'-O-(3-Thiotriphosphate)