1,2,4-Triazolyl octahydropyrrolo[2,3-b]pyrroles: A new series of potent and selective dopamine D3 receptor antagonists |
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| Affiliation: | 1. Aptuit s.r.l, Via Fleming 4, 37135 Verona, Italy;2. Indivior Inc, The Fairfax Building, 10710 Midlothian Turnpike, Suite 430, Richmond, VA 23235, USA;1. Department of Drug Technology and Pharmaceutical Biotechnology, Faculty of Pharmacy, Medical University of Warsaw, 1 Banacha Street, 02-097 Warsaw, Poland;2. Jagiellonian University Medical College, Department of Clinical Pharmacy, 9 Medyczna Street, 30-688 Kraków, Poland;3. Isobolographic Analysis Laboratory, Institute of Rural Health, 2 Jaczewskiego Street, 20-950 Lublin, Poland;4. Department of Pathophysiology, Medical University, 8 Jaczewskiego Street, 20-090 Lublin, Poland;5. Department of Physiopathology, Institute of Rural Health, 2 Jaczewskiego Street, 20-950 Lublin, Poland;6. Department of Pharmacobiology, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland;7. Department of Pharmaceutical Chemistry, Medical University of Gdańsk, 107 Al. Gen. J. Hallera Street, 80-416 Gdańsk, Poland;1. Department of Bioorganic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland;2. Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland;3. Department of Toxicology, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland;4. Laboratory of Pharmacological Screening, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland;5. Department of Chemistry, Institute of Biology, Pedagogical University, Podchorążych 2, 30-084 Krakow, Poland;6. Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Krakow, Poland;1. Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, 3307 N. Broad Street, Philadelphia, PA, USA;2. Cureveda, LLC, 1450 South Rolling Road, Halethorpe, MD 21227, USA;3. Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Baltimore, MD 21205, USA;4. Department of Chemistry, Temple University, Philadelphia, PA 19122, USA;1. Xenon Pharmaceuticals Inc., 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada;2. Novartis Institute for Biomedical Research, 250 Massachusetts Ave, Cambridge, MA 02139, USA |
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| 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. |
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| Keywords: | Dopamine DA D3 receptor Antagonist Addiction Neuroscience |
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