title: Studies on selectin blocker. 9. SARs of non-sugar selectin blocker against E-, P-, L-selectin bindings.
abstract: As a part of study of selectin blockers, we have already reported that a non-sugar selectin antagonist (3) was successfully discovered using a computational screening (Hiramatsu, Y.; Tsukida, T.; Nakai, Y.; Inoue, Y.; Kondo, H. J. Med. Chem. 2000, 43, 1476). To investigate the SARs of compound 3 against E-, P-, and L-selectins, we synthesized the derivatives of compound 3 and evaluated their inhibitory activities toward selectin bindings. The structural diversity of compound 3 contained the following: (1) a modification of the spacer unit (4--7), (2) a modification of the tail unit (8--11), (3) a modification of the head unit (12--18). As a result, it was found that a non-sugar based selectin blocker (3) could be a potential lead compound for E-, P-, and L-selectin blockers and some of the derivatives showed broad and/or selective inhibitory activities toward the E-, P-, and L-selectins. In addition, it was found that the experimental evidence well supported that the computational screening using 3D-pharmacophore model could be useful methodology to find out a new lead for the several type of selectin blockers, which included a broad and/or a selective inhibitor.
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: H
authors.initials: H
authors.lastname: Moriyama
authors.forename: Y
authors.initials: Y
authors.lastname: Hiramatsu
authors.forename: T
authors.initials: T
authors.lastname: Kiyoi
authors.forename: T
authors.initials: T
authors.lastname: Achiha
authors.forename: Y
authors.initials: Y
authors.lastname: Inoue
authors.forename: H
authors.initials: H
authors.lastname: Kondo
mesh_terms: D001549:Benzamides / Q000737:chemistry; D001565:Benzoates / Q000737:chemistry; D002241:Carbohydrates / Q000737:chemistry; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D019087:Selectins / Q000187:drug effects* / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: C407509:3-(4-octadecanoylaminobenzoylamino)-3',4-oxydibenzoic acid; D001549:Benzamides; D001565:Benzoates; D002241:Carbohydrates; D019087:Selectins