1, 2, 4-Triazolyl octahydropyrrolo[2, 3-b]pyrroles: A new series of potent and selective dopamine D3 receptor antagonists. Issue 8 (15th April 2016)

• Record Type: Journal Article
• Authors: Micheli, Fabrizio; Bernardelli, Andrea; Bianchi, Federica; Braggio, Simone; Castelletti, Laura; Cavallini, Palmina; Cavanni, Paolo; Cremonesi, Susanna; Cin, Michele Dal; Feriani, Aldo; Oliosi, Beatrice; Semeraro, Teresa; Tarsi, Luca; Tomelleri, Silvia; Wong, Andrea; Visentini, Filippo; Zonzini, Laura; Heidbreder, Christian
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 8(2016)
• Page Start: 1619
• Page End: 1636
• Publication Date: 2016-04-15
• Subjects: Dopamine -- DA D3 receptor -- Antagonist -- Addiction -- Neuroscience; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.02.031
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: A novel series of 1, 2, 4-triazolyl octahydropyrrolo[2, 3- b ]pyrroles showing high affinity and selectivity at the DA D3 receptor is reported here. Compounds endowed with high selectivity over the hERG channel were identified and their pharmacokinetic properties thoroughly analyzed. A few derivatives with appropriate developability characteristics were selected for further studies and progression along the screening cascade. In particular, derivative60a, (DA D3 p K i = 8.4, DA D2 p K i = 6.0 and hERG fp K i = 5.2) showed a balanced profile and further refinements are in progress around this molecule.