Studies on selectin blocker. 9. SARs of non-sugar selectin blocker against E-, P-, L-selectin bindings

Bioorg Med Chem. 2001 Jun;9(6):1479-91. doi: 10.1016/s0968-0896(01)00023-2.

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.

MeSH terms

  • Benzamides / chemistry
  • Benzoates / chemistry
  • Carbohydrates / chemistry
  • Drug Design
  • Drug Evaluation, Preclinical / methods
  • Inhibitory Concentration 50
  • Models, Molecular
  • Selectins / drug effects*
  • Selectins / metabolism*
  • Structure-Activity Relationship

Substances

  • 3-(4-octadecanoylaminobenzoylamino)-3',4-oxydibenzoic acid
  • Benzamides
  • Benzoates
  • Carbohydrates
  • Selectins