1. 1,2,4-Triazolyl octahydropyrrolo[2,3-b]pyrroles: A new series of potent and selective dopamine D3 receptor antagonists
- Author
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Michele Dal Cin, Susanna Cremonesi, Simone Braggio, Andrea Wong, Aldo Feriani, Laura Zonzini, Andrea Bernardelli, Laura Castelletti, Federica Bianchi, Filippo Visentini, Palmina Cavallini, Teresa Semeraro, Silvia Tomelleri, Luca Tarsi, Christian Heidbreder, Paolo Cavanni, Fabrizio Micheli, and Beatrice Oliosi
- Subjects
0301 basic medicine ,Models, Molecular ,Stereochemistry ,Clinical Biochemistry ,hERG ,Pharmaceutical Science ,CHO Cells ,01 natural sciences ,Biochemistry ,Binding, Competitive ,03 medical and health sciences ,Structure-Activity Relationship ,Cricetulus ,Dopamine receptor D3 ,Dopamine ,Drug Discovery ,medicine ,Structure–activity relationship ,Animals ,Humans ,Pyrroles ,Molecular Biology ,biology ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Chemistry ,Chinese hamster ovary cell ,Organic Chemistry ,Antagonist ,Receptors, Dopamine D3 ,Triazoles ,biology.organism_classification ,Ether-A-Go-Go Potassium Channels ,0104 chemical sciences ,030104 developmental biology ,HEK293 Cells ,biology.protein ,Molecular Medicine ,Selectivity ,medicine.drug - 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, derivative 60a, (DA D3 pKi=8.4, DA D2 pKi=6.0 and hERG fpKi=5.2) showed a balanced profile and further refinements are in progress around this molecule.
- Published
- 2016