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

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.

An isolated, surface-expressed I domain of the integrin αLβ2 is sufficient for strong adhesive function when locked in the open conformation with a disulfide bond

“…Thus, the mode of action by lovastatin is to stabilize the I domain in the closed conformation and block the downward shift of the C-terminal ␣-helix along the side of the I domain that occurs in the transition to the open conformation. Recently, other structural classes of small molecules have been described that antagonize the function of ␣L␤2 (39,40). It will be interesting to determine their mechanism of action.…”

Leukocyte Function-associated Antigen 1-mediated Adhesion Stability Is Dynamically Regulated through Affinity and Valency during Bond Formation with Intercellular Adhesion Molecule-1

“…We present here a new small molecule allosteric inhibitor that targets the IDAS and downshifts LFA-1 from a high to intermediate affinity. This small molecule is similar to the diaryl sulfide cinnamide antagonists (13). Allosteric small molecules provide a powerful tool for directing leukocyte adhesion; however, the interrelationships between bond kinetics, LFA-1 conformation, valence in binding ICAM-1, and adhesion stability remain ill-defined.…”

Microwave‐Assisted Cross‐Coupling for the Construction of Diaryl Sulfides

“…Aryl sulfides and their oxidized forms, sulfones and sulfoxides, are common functional groups in pharmaceutical agents such as nonsteroidal anti-inflammatory agents, 1 HIV protease inhibitors and antiviral agents, 2 selective M 2 muscarinic receptor antagonists, 3 leukocyte function-associated antigen-1/intracellular molecule-1 interaction antagonists, 4 leukotriene B 4 antagonists, 5 histone deacetylase inhibitors, 6 fatty acid amide hydrolase inhibitors, 7 a 2 -adrenoceptor antagonists, 8 and gonadotropin-releasing hormone antagonists. 9 Most importantly, diaryl sulfides serve as useful starting materials for the construction of heterocycles containing sulfur atom and precursors leading to sulfones and sulfoxides.…”

“…Although moderate to high yields can be obtained, often harsh reaction conditions or long reaction times are needed in these methods. [18][19][20] Migita and co-workers reported the first cross-coupling reaction of aryl halides and thiols for the construction of aryl-sulfur bond by using catalyst Pd(PPh 3 ) 4 and base NaOt-Bu in ethanol at reflux or in DMSO at 90°C. 21 Recently, catalysts containing transition metals such as palladium, 22,23 cobalt, 24 nickel, 25 and copper 19,26 have been capitalized in the condensation reactions of thiolates and aryl halides.…”