Deuteration and fluorination of 1,3-bis(2-phenylethyl)pyrimidine-2,4,6(1H,3H,5H)-trione to improve its pharmacokinetic properties |
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| Institution: | 1. Department of Chemistry, Northwestern University, Evanston, IL 60208-3113, USA;2. Cambria Pharmaceuticals, Cambridge, MA 02142, USA;3. Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL 60208-3500, USA;4. Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, IL 60208-3113, USA;1. Optical Radiation Standards, CSIR National Physical Laboratory, Dr. K.S. Krishnan Road, New Delhi, India;2. Quantum Optics and Photon Physics, CSIR-National Physical Laboratory, Dr. K.S. Krishnan Road, New Delhi, India;1. Discovery Chemistry, Merck Research Laboratory, Kenilworth, NJ 07033, United States;2. Department of Medicinal Chemistry, Albany Molecular Research, Inc. (AMRI), Albany, NY 12203, United States;3. In Vivo Pharmacology Group, Merck Research Laboratory, Kenilworth, NJ 07033, United States;4. Cardiorenal Group, Merck Research Laboratory, Kenilworth, NJ 07033, United States;5. Neuroscience, Merck Research Laboratory, West Point, PA 19486, United States;6. Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratory, Kenilworth, NJ 07033, United States;1. Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA;2. WuXi AppTec Co., Ltd, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, PR China;1. Université de Nantes, Nantes Atlantique Universités, Laboratoire de Chimie Thérapeutique, Cibles et Médicaments des Infections et du Cancer, IICIMED-EA 1155, UFR Sciences Pharmaceutiques, 1 rue Gaston Veil, Nantes F-44035 Cedex 1, France;2. Protein Phosphorylation & Human Disease Group, CNRS, USR 3151, Station Biologique, B.P. 74, 29682 Roscoff Cedex, France;3. Plate-forme ImPACcell, UMS-3480, Université de Rennes 1, Campus de Villejean, 2 avenue du Professeur Léon Bernard, 35043 Rennes Cedex, France;4. Centre de Biophysique Moléculaire, CNRS, UPR 4301, Université d’Orléans et INSERM, rue Charles Sadron, 45071 Orléans Cedex 2, France;5. ManRos Therapeutics, Centre de Perharidy, 29680 Roscoff, France;1. AstraZeneca, Department of Medicinal Chemistry, Montréal H4S 1Z9, Canada;2. AstraZeneca/OmegaChem, Department of Medicinal Chemistry, Montréal H4S 1Z9, Canada;3. AstraZeneca, Department of Bioscience, Montréal H4S 1Z9, Canada;4. Astrazeneca, DMPK, Montréal H4S 1Z9, Canada;1. Department of Chemistry, University of Louisville, Louisville, KY 40292, United States;2. Department of Chemistry and Physics, Bellarmine University, Louisville, KY 40205, United States;3. College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, China |
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| Abstract: | Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons, leading to muscle weakness, paralysis, and death, most often from respiratory failure. Over 200 pyrimidine-2,4,6-trione (PYT) small molecules, which prevent aggregation and reduce the associated toxicity of mutant superoxide dismutase 1 (SOD1) found in patients with familial ALS, have been synthesized and tested. One of the compounds (1,3-bis(2-phenylethyl)pyrimidine-2,4,6(1H,3H,5H)-trione, (1) was previously found to have an excellent combination of potency efficacy, and some desirable pharmacokinetic properties. To improve the solubility and metabolic stability properties of this compound, deuterium and fluorine were introduced into 1. New analogs with better solubility, plasma stability, and human microsome stability were identified. |
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| Keywords: | Pyrimidine-2 4 6-triones (PYT) Amyotrophic lateral sclerosis (ALS) Fluorination Deuteration ADME Microsome stability Pharmacokinetics |
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