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 C=O...S interaction in 1, whereas thiazoles 2 showed a repulsive C=O...N interaction.
Nettekoven
Matthias
M
F. Hoffmann-La Roche Ltd, Pharmaceutical Research Basel, Discovery Chemistry, CH-4070 Basel, Switzerland. matthias.nettekoven@roche.com
Guba
Wolfgang
W
Neidhart
Werner
W
Mattei
Patrizio
P
Pflieger
Philippe
P
Roche
Olivier
O
Taylor
Sven
S
D017076:Computer-Aided Design; D018360:Crystallography, X-Ray; D007536:Isomerism; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000494:pharmacology*
D008024:Ligands; D017476:Receptors, Neuropeptide Y; D013844:Thiazoles; C100568:neuropeptide Y5 receptor