Study on Selectin Blocker. 8. Lead Discovery of a Non-Sugar Antagonist Using a 3D-Pharmacophore Model

• Published in: Journal of medicinal chemistry 2000-04, Vol.43 (8), p.1476-1483
• Main Authors: Hiramatsu, Yasuyuki, Tsukida, Takahiro, Nakai, Yoshiyuki, Inoue, Yoshimasa, Kondo, Hirosato
• Format: Article
• Language: English
• Subjects: Benzamides - chemical synthesis; Benzamides - chemistry; Benzoates - chemical synthesis; Benzoates - chemistry; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Carbohydrate Sequence; Databases, Factual; E-Selectin - chemistry; Medical sciences; Models, Molecular; Molecular Conformation; Molecular Sequence Data; Pharmacology. Drug treatments; Selectins - chemistry
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm990342j

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 (sLex), we have already found a potent compound, a sulfated Lex 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 IC50 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.