1,2,4-Triazolyl octahydropyrrolo[2,3-b]pyrroles: A new series of potent and selective dopamine D3 receptor antagonists

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• 作者：Fabrizio Micheli^a ; ^{fabrizio.micheli@aptuit.com" class="auth_mail" title="E-mail the corresponding author} ; Andrea Bernardelli^a ; Federica Bianchi^a ; Simone Braggio^a ; Laura Castelletti^a ; Palmina Cavallini^a ; Paolo Cavanni^a ; Susanna Cremonesi^a ; Michele Dal Cin^a ; Aldo Feriani^a ; Beatrice Oliosi^a ; Teresa Semeraro^a ; Luca Tarsi^a ; Silvia Tomelleri^a ; Andrea Wong^a ; Filippo Visentini^a ; Laura Zonzini^a ; Christian Heidbreder^b
• 关键词：Dopamine ; DA D3 receptor ; Antagonist ; Addiction ; Neuroscience
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：15 April 2016
• 年：2016
• 卷：24
• 期：8
• 页码：1619-1636
• 全文大小：1116 K

文摘

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, derivative 60a, (DA D3 pK_i = 8.4, DA D2 pK_i = 6.0 and hERG fpK_i = 5.2) showed a balanced profile and further refinements are in progress around this molecule.