The trifluoromethylphenyl P2 motif from previously reported heteroarylnitrile series has been successfully applied for the design and synthesis of highly potent novel ketoamide-based cathepsin S inhibitors. The key in this process is the change of the torsion angle between the P2 phenyl ring and the attached secondary amide by adding a small Cl, F, or Me group at the 2-position.
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Synthesis of α-Ketoamide-Based Stereoselective Calpain-1 Inhibitors as Neuroprotective Agents.
ChemMedChem
December 2020
Department of Pharmaceutical Sciences, University of Illinois at Chicago, 833 S. Wood Street, Chicago, IL., 60612, USA.
Calpain inhibitors have been proposed as drug candidates for neurodegenerative disorders, with ABT-957 entering clinical trials for Alzheimer's disease and mild cognitive impairment. The structure of ABT-957 was very recently disclosed, and trials were terminated owing to inadequate CNS concentrations to obtain a pharmacodynamic effect. The multistep synthesis of an α-ketoamide peptidomimetic inhibitor series potentially including ABT-957 was optimized to yield diastereomerically pure compounds that are potent and selective for calpain-1 over papain and cathepsins B and K.
View Article and Find Full Text PDFPharmacological Inhibition of Cathepsin S Suppresses Abdominal Aortic Aneurysm in Mice.
Eur J Vasc Endovasc Surg
June 2020
Cardiovascular Research Centre, College of Medicine, National Cheng Kung University, Taiwan; Department of Physiology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Orthopaedic Research Centre, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address:
Objective: Evidence suggests that cathepsin S (CTSS), a potent mammalian elastase, participates in abdominal aortic aneurysm (AAA) formation. This study examines the hypothesis that pharmacological inhibition of CTSS with an α-ketoamide based compound 6r might suppress AAA in mice.
Methods: Experimental study of the CaCl induced AAA model in B6 mice and angiotensin II (AngII) infused AAA model in ApoE mice.
Discovery of Novel and Highly Selective Inhibitors of Calpain for the Treatment of Alzheimer's Disease: 2-(3-Phenyl-1H-pyrazol-1-yl)-nicotinamides.
J Med Chem
August 2017
Neuroscience Research, AbbVie Deutschland GmbH & Co. KG , Knollstrasse, 67061 Ludwigshafen, Germany.
Calpain overactivation has been implicated in a variety of pathological disorders including ischemia/reperfusion injury, cataract formation, and neurodegenerative diseases such as Alzheimer's disease (AD). Herein we describe our efforts leading to the identification of ketoamide-based 2-(3-phenyl-1H-pyrazol-1-yl)nicotinamides as potent and reversible inhibitors of calpain with high selectivity versus related cysteine protease cathepsins, other proteases, and receptors. Broad efficacy in a set of preclinical models relevant to AD suggests that inhibition of calpain represents an attractive approach with potential benefit for the treatment of AD.
View Article and Find Full Text PDFTrifluoromethylphenyl as P2 for ketoamide-based cathepsin S inhibitors.
Bioorg Med Chem Lett
December 2010
Merck Research Laboratories, MSD, Newhouse, Lanarkshire, United Kingdom.
The trifluoromethylphenyl P2 motif from previously reported heteroarylnitrile series has been successfully applied for the design and synthesis of highly potent novel ketoamide-based cathepsin S inhibitors. The key in this process is the change of the torsion angle between the P2 phenyl ring and the attached secondary amide by adding a small Cl, F, or Me group at the 2-position.
View Article and Find Full Text PDFAcyclic, orally bioavailable ketone-based cathepsin K inhibitors.
Bioorg Med Chem Lett
January 2007
Department of Medicinal Chemistry, GlaxoSmithKline, Research Triangle Park, NC 27709, USA.
Starting from a potent ketone-based inhibitor with poor drug properties, incorporation of P(2)-P(3) elements from a ketoamide-based inhibitor led to the identification of a hybrid series of ketone-based cathepsin K inhibitors with better oral bioavailability than the starting ketone.
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