1,2,4-Triazolyl 5-Azaspiro[2.4]heptanes: Lead Identification and Early Lead Optimization of a New Series of Potent and Selective Dopamine D3 Receptor Antagonists

著者: Fabrizio Micheli*†, Alessia Bacchi§, Simone Braggio†, Laura Castelletti†, Palmina Cavallini†, Paolo Cavanni†, Susanna Cremonesi†, Michele Dal Cin†, Aldo Feriani†, Sylvie Gehanne†, Mahmud Kajbaf†, Luciano Marchió§, Selena Nola†, Beatrice Oliosi†, Annalisa Pellacani†, Elisabetta Perdonà†, Anna Sava†, Teresa Semeraro†, Luca Tarsi†, Silvia Tomelleri†, Andrea Wong†, Filippo Visentini†, Laura Zonzini† and Christian Heidbreder‡

A novel series of 1,2,4-triazolyl 5-azaspiro[2.4]heptanes with high affinity and selectivity at the dopamine (DA) D3 receptor (D3R) is described. Some of these compounds also have high selectivity over the hERG channel and were characterized with respect to their pharmacokinetic properties both in vitro and in vivo during lead identification and early lead optimization phases. A few derivatives with overall favorable developability characteristics were selected for further late lead optimization studies.