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Discovery of ABT-957: 1-Benzyl-5-oxopyrrolidine-2-carboxamides as selective calpain inhibitors with enhanced metabolic stability
Institution:1. AbbVie Deutschland GmbH & Co. KG, Neuroscience Research, Knollstrasse, 67061 Ludwigshafen, Germany;2. AbbVie Deutschland GmbH & Co. KG, DMPK-BA, Knollstrasse, 67061 Ludwigshafen, Germany;3. AbbVie Inc., 1 North Waukegan Road, North Chicago, IL 60064-6125, United States;1. Novartis Pharma AG, Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland;2. Novartis Institutes for BioMedical Research, Ohkubo 8, Tsukuba, Ibaraki 300-2611, Japan;1. Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, MA 02210, USA;2. Vertex Pharmaceuticals Canada Incorporated, 275 Boul. Armand-Frappier, Laval, QC H7V 4A7, Canada;1. Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA;2. NCI Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA;3. Sanford Children’s Health Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA;1. Department of Medicinal Chemistry, Respiratory Inflammation and Autoimmunity Innovative Medicines, AstraZeneca R&D, Pepparedsleden 1, SE-431 83 Mölndal, Sweden;2. Department of Medicinal Chemistry, AstraZeneca R&D Lund, Scheelevägen 1, SE-221 87 Lund, Sweden;1. Rare and Neurologic Disease Research, Sanofi, 1 av Pierre Brossolette, Chilly Mazarin F-91935, France;2. Medicinal Chemistry, Sanofi, 1 av Pierre Brossolette, Chilly Mazarin F-91385, France;3. DMPK, Sanofi, 13 quai Jules Guesde, Vitry-sur-Seine F-94403, France;4. Preclinical Safety, Sanofi, 3, digue d’ Alfortville, Alfortville F-94140, France;5. Translational Science, Sanofi, 1 av Pierre Brossolette, Chilly Mazarin F-91385, France;6. CNS Department, Sanofi, 195 route d’Espagne, F-31036 Toulouse, France;7. CNS Department, 13, quai Jules Guesde, F-94403 Vitry-sur-Seine Cedex, France
Abstract:Aberrant activation of calpain has been observed in various pathophysiological disorders including neurodegenerative diseases such as Alzheimer’s Disease. Here we describe our efforts on ketoamide-based 1-benzyl-5-oxopyrrolidine-2-carboxamides as a novel series of highly selective calpain inhibitors mitigating the metabolic liability of carbonyl reduction. The most advanced compound from this new series, namely A-1212805 (ABT-957, Alicapistat) proceeded to clinical phase I studies.
Keywords:Calpain inhibition  Cysteine protease inhibition  Ketoamide  Alzheimer’s Disease
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