Solid phase parallel synthesis of highly substituted thiophene derivatives and identification of novel phosphodiesterase-4 (PDE-4) inhibitors

A versatile protocol for solid phase synthesis of highly substituted thiophene derivatives and their activity against the PDE-4 enzyme are discussed. This protocol employs 3-hydroxymethylthiophene-2-boronic acid (5) as the scaffold and sequential palladium catalyzed cross-coupling reactions as the C-C bond forming step. This methodology allows convenient modification of the thiophene core from three directions, giving rise to structurally diverse derivatives with overall high chemical purity and yield. A novel series of potent PDE-4 inhibitors have been identified from these compounds. (C) 1999 Published by Elsevier Science Ltd. All rights reserved.