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

• Published in: Journal of medicinal chemistry Vol. 59; no. 18; pp. 8549 - 8576
• Main Authors: Micheli, Fabrizio, Bacchi, Alessia, Braggio, Simone, Castelletti, Laura, Cavallini, Palmina, Cavanni, Paolo, Cremonesi, Susanna, Dal Cin, Michele, Feriani, Aldo, Gehanne, Sylvie, Kajbaf, Mahmud, Marchió, Luciano, Nola, Selena, Oliosi, Beatrice, Pellacani, Annalisa, Perdonà, Elisabetta, Sava, Anna, Semeraro, Teresa, Tarsi, Luca, Tomelleri, Silvia, Wong, Andrea, Visentini, Filippo, Zonzini, Laura, Heidbreder, Christian
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 22.09.2016; Amer Chemical Soc
• Subjects: Animals; Chemistry, Medicinal; CHO Cells; Cricetulus; Crystallography, X-Ray; Ether-A-Go-Go Potassium Channels - metabolism; Heptanes - chemistry; Heptanes - pharmacology; Humans; Life Sciences & Biomedicine; Models, Molecular; Pharmacology & Pharmacy; Receptors, Dopamine D3 - antagonists & inhibitors; Receptors, Dopamine D3 - metabolism; Science & Technology; Spiro Compounds - chemistry; Spiro Compounds - pharmacology; Structure-Activity Relationship; Triazoles - chemistry; Triazoles - pharmacology; D-3 RECEPTORS; LINKING; DESIGN; ENERGY; CRYSTAL-STRUCTURE; HIGH-AFFINITY; DISORDERS; OCCUPANCY; ADDICTION; DISCOVERY
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.6b00972

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.