title: Pharmacophore-based design of sphingosine 1-phosphate-3 receptor antagonists that include a 3,4-dialkoxybenzophenone scaffold.
abstract: Sphingosine 1-phosphate (S1P) receptors are G-protein-coupled receptors. Among the five identified subtypes S1P1-5, the S1P3 receptor expressed on vascular endothelial cells has been shown to play an important role in cell proliferation, migration, and inflammation. A pharmacophore-based database search was used to identify a potent scaffold for an S1P3 receptor antagonist by common feature-based alignment and further validated using the Güner-Henry (GH) scoring method. Assumed excluded volumes were merged into this model to evaluate the steric effect with the S1P3 receptor. Three commercially available compounds were identified as S1P3 receptor antagonists, with IC50 values <5 microM. The synthesis of further derivatives revealed that the 3,4-dialkoxybenzophenone scaffold is a potent component of an S1P3 receptor antagonist. Our results indicate that pharmacophore-based design of S1P3 receptor antagonists can be used to expand the possibility of structural modification through scaffold-hopping based on a database search.
authors.affiliation: Drug Research Department, Tokyo Research Laboratories, TOA EIYO Ltd., 2-293-3 Amanuma, Oomiya, Saitama 330-0834, Japan. koide.yuuki@toaeiyo.co.jp
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Koide
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Uemoto
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hasegawa
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Sada
authors.forename: Akira
authors.initials: A
authors.lastname: Murakami
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takasugi
authors.forename: Atsuko
authors.initials: A
authors.lastname: Sakurai
authors.forename: Naoki
authors.initials: N
authors.lastname: Mochizuki
authors.forename: Atsuo
authors.initials: A
authors.lastname: Takahashi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nishida
mesh_terms: D000818:Animals; D001577:Benzophenones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D016208:Databases, Factual; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D021281:Quantitative Structure-Activity Relationship; D049349:Receptors, Lysosphingolipid / Q000819:agonists / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D014162:Transfection
chemical_list: D001577:Benzophenones; D049349:Receptors, Lysosphingolipid; D002118:Calcium