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Discovery of Novel P-Arylthio Cinnamides as Antagonists of Leukocyte Function-Associated antigen-1/intracellular Adhesion molecule-1 Interaction. 1. Identification of an Additional Binding Pocket Based on an Anilino Diaryl Sulfide Lead

Discovery of Novel P-Arylthio Cinnamides as Antagonists of Leukocyte Function-Associated antigen-1/intracellular Adhesion molecule-1 Interaction. 1. Identification of an Additional Binding Pocket Based on an Anilino Diaryl Sulfide Lead

G Liu, J T Link, Z Pei, E B Reilly, S Leitza, B Nguyen, K C Marsh, G F Okasinski, T W von Geldern, M Ormes, K Fowler, M Gallatin

J Med Chem. 2000 Oct 19;43(21):4025-40.

PMID: 11052808

Abstract:

The interaction between leukocyte function-associated antigen-1 (LFA-1), a member of the beta(2)-integrin family of adhesion molecules, and intracellular adhesion molecule ICAM-1 (cd54) is thought to play a critical role in the inflammatory process. On the basis of an anilino diaryl sulfide screening lead 1, in combination with pharmacophore analysis of other screening hits, we have identified an adjacent binding pocket. Subsequently, a p-ethenylcarbonyl linker was discovered to be optimal for accessing this binding site. Solution-phase parallel synthesis enabled rapid optimization of the cinnamides for this pocket. In conjunction with fine-tuning of the diaryl substituents, we discovered a novel series of potent, nonpeptide inhibitors of LFA-1/ICAM-1 interaction, exemplified by A-286982 (28h), which has IC(50) values of 44 and 35 nM in an LFA-1/ICAM-1 binding assay and LFA-1-mediated cellular adhesion assay, respectively.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP280749179	A-286982		280749-17-9	Price

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