作者: Jürgen Bajorath ; Hiroyuki Kouji ; Yuji Kogami ; Takeshi Himeno ; Takeo Harada ; Kazuo Yano ; Miyuki Shoda ; Florence L. Stahura ; Satoshi Shiojiri

AbstractThe binding of lymphocyte function‐associated antigen‐1 (LFA‐1) to its ligand on endothelial cells, intercellular adhesion molecule‐1 (ICAM‐1), is a crucial step in the migration of leukocytes during the early stages of inflammation and is also involved in T‐cell activation. In this paper, we report the identification of a series of novel antagonists of the LFA‐1/ICAM‐1 interaction using ligand‐based virtual screening (VS), analogue design, and structure–activity relationship (SAR) analysis. Candidate compounds were evaluated in protein binding and cell adhesion assays. Experimental evaluation of only 25 candidates selected from a pool of ∼2.5 million database compounds identified an initial hit that could be expanded and converted into a lead that effectively blocked the interaction between LFA‐1 and ICAM‐1.

2001-12-01·Journal of Medicinal Chemistry1区 · 医学

Discovery of Novel p-Arylthio Cinnamides as Antagonists of Leukocyte Function-Associated Antigen-1/Intercellular Adhesion Molecule-1 Interaction. 4. Structure−Activity Relationship of Substituents on the Benzene Ring of the Cinnamide

1区 · 医学

Article

作者: Leitza, Sandra ; Lynch, John ; Freeman, Jennifer ; Dickinson, Robert ; Reilly, Edward B. ; Liu, Gang ; Okasinski, Gregory F. ; DeVries, Peter ; Xin, Zhili ; Huth, Jeffrey R. ; Mussatto, Donna ; Jae, Hwan-Soo ; Pei, Zhonghua ; Kester, Jeff ; Winn, Martin ; von Geldern, Thomas W.

We have shown that p-arylthio cinnamides can inhibit the interaction of LFA-1 and ICAM-1, which is involved in cell adhesion and the inflammatory process. We now show that 2,3-disubstitution on the aryl portion of the cinnamide results in enhanced activity over mono substitution on the ring. The best 2,3-substituents were chlorine and trifluoromethyl groups. Compounds 39 and 40 which contain two CF3 groups have IC(50) values of 0.5 and 0.1 nM, respectively, in inhibiting JY8 cells expressing LFA-1 on their surface, from adhering to ICAM-1. The structure-activity relationship (SAR) was examined using an NMR based model of the LFA-1 I domain/compound 31 complex. One of our compounds (38) was able to reduce cell migration in two different in vivo experiments.

2001-08-01·Journal of Medicinal Chemistry1区 · 医学

Discovery of Potent Antagonists of Leukocyte Function-Associated Antigen-1/Intercellular Adhesion Molecule-1 Interaction. 3. Amide (C-Ring) Structure−Activity Relationship and Improvement of Overall Properties of Arylthio Cinnamides

1区 · 医学

Article

作者: Marsh, Kennan C. ; Gao, Yi ; Li, Yihong ; Link, James T. ; Pei, Zhonghua ; Liu, Gang ; Cox, Bryan F. ; Xin, Zhili ; Huth, Jeffery R. ; Reilly, Edward B. ; Okasinski, Greg F. ; DeVries, Peter ; von Geldern, Thomas W. ; Lubbers, Nathan L. ; Leitza, Sandra

The interaction of LFA-1 and ICAM-1 plays an important role in the cell adhesion process. On the basis of previously reported SAR and structural information on the binding of our p-arylthiocinnamide series to LFA-1, we have identified the cyclic amide (C-ring) as a site for modification. Improvement in potency and, more importantly, in the physical properties and pharmacokinetic profiles of the leading compounds resulted from this modification. One of the best compounds (11f) is also shown to reduce myocardial infarct size in rat.

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