Isomeric thiazole derivatives as ligands for the neuropeptide Y5 receptor

Sets of isomeric thiazole derivatives 1 and 2 have been synthesised in a parallel iterative solution-phase synthesis approach guided by the SAR analysis derived from biological results and computer-aided design and analysis. This synergistic and streamlined working procedure led to highly active isomeric NPY5 receptor ligands. However, a 10-fold difference at least in their respective binding affinities was consistently found for all isomeric pairs 1 and 2. The analysis of conformational differences due to heteroatom interactions in 1 and 2 revealed a favourable CO⋯S interaction in 1, whereas thiazoles 2 showed a repulsive CO⋯N interaction.

Graphical abstractSets of isomeric thiazole derivatives 1 and 2 were synthesised and compared with respect to their conformational energies.Figure optionsDownload full-size imageDownload as PowerPoint slide