928199-44-4Relevant articles and documents
Structure-activity relationships of a small-molecule inhibitor of the PDZ domain of PICK1
Bach, Anders,Stuhr-Hansen, Nicolai,Thorsen, Thor S.,Bork, Nicolai,Moreira, Irina S.,Frydenvang, Karla,Padrah, Shahrokh,Christensen, S. Brogger,Madsen, Kenneth L.,Weinstein, Harel,Gether, Ulrik,Stromgaard, Kristian
supporting information; experimental part, p. 4281 - 4288 (2010/11/05)
Recently, we described the first small-molecule inhibitor, (E)-ethyl 2-cyano-3-(3,4-dichlorophenyl)acryloylcarbamate (1), of the PDZ domain of protein interacting with Cα-kinase 1 (PICK1), a potential drug target against brain ischemia, pain and cocaine addiction. Herein, we explore structure-activity relationships of 1 by introducing subtle modifications of the acryloylcarbamate scaffold and variations of the substituents on this scaffold. The configuration around the double bond of 1 and analogues was settled by a combination of X-ray crystallography, NMR and density functional theory calculations. Thereby, docking studies were used to correlate biological affinities with structural considerations for ligand-protein interactions. The most potent analogue obtained in this study showed an improvement in affinity compared to 1 and is currently a lead in further studies of PICK1 inhibition.
