title: Study on selectin blocker. 8. Lead discovery of a non-sugar antagonist using a 3D-pharmacophore model.
abstract: We have developed a pharmacophore model of a ligand/E-selectin complex to screen drug candidates for selectin blockers. In a series of sugar mimetic studies of the E-selectin ligand, sialyl Lewis X (sLe(x)), we have already found a potent compound, a sulfated Le(x) analogue (1), and also have proposed how compound 1 binds to E-selectin (Tsujishita, H.; Hiramatsu, Y.; Kondo, N.; Ohmoto, H.; Kondo, H.; Kiso, M.; Hasegawa, A. J. Med. Chem. 1997, 40, 362-369). To find drug candidates that fit into the binding pocket of E-selectin, we constructed an original 3D-pharmacophore model from structural information of a compound 1/E-selectin complex model and screened lead compounds for selectin blockers using a commercially available database ACD-3D. As a result, we discovered a lead compound (2) containing good selectin inhibitory activity, and in addition, we succeeded to preliminarily optimize it to a more active lead compound (3) with micromolar IC(50) values, based on the 3D-pharmacophore model investigation. This methodology using the 3D-pharmacophore model could be applicable as a pre-screen system for selectin blockers.
authors.affiliation: Department of Chemistry, Nippon Organon K.K., R&D Laboratories, 1-5-90 Tomobuchi-Cho, Miyakojima-Ku, Osaka 534-0016, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Hiramatsu
authors.forename: T
authors.initials: T
authors.lastname: Tsukida
authors.forename: Y
authors.initials: Y
authors.lastname: Nakai
authors.forename: Y
authors.initials: Y
authors.lastname: Inoue
authors.forename: H
authors.initials: H
authors.lastname: Kondo
mesh_terms: D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry; D001565:Benzoates / Q000138:chemical synthesis* / Q000737:chemistry; D002240:Carbohydrate Sequence; D016208:Databases, Factual; D019040:E-Selectin / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D019087:Selectins / Q000737:chemistry*
chemical_list: C407509:3-(4-octadecanoylaminobenzoylamino)-3',4-oxydibenzoic acid; D001549:Benzamides; D001565:Benzoates; D019040:E-Selectin; D019087:Selectins