270064-55-6Relevant articles and documents
Studies on selectin blocker. 9. SARs of non-sugar selectin blocker against E-, P-, L-selectin bindings
Moriyama, Hideki,Hiramatsu, Yasuyuki,Kiyoi, Takao,Achiha, Toshio,Inoue, Yoshimasa,Kondo, Hirosato
, p. 1479 - 1491 (2007/10/03)
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.; Inou, 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) and modification of the spacer unit (4-7), (2) a modification of the tail (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 wome 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. Copyright
Study on selectin blocker. 8. Lead discovery of a non-sugar antagonist using a 3D-pharmacophore model
Hiramatsu, Yasuyuki,Tsukida, Takahiro,Nakai, Yoshiyuki,Inoue, Yoshimasa,Kondo, Hirosato
, p. 1476 - 1483 (2007/10/03)
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 I 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.