Abstract
We describe here a novel 4-amino-2-cyanopyrimidine scaffold for nonpeptidomimetic cathepsin S selective inhibitors. Some of the synthesized compounds have sub-nanomolar potency and high selectivity toward cathepsin S along with promising pharmacokinetic and physicochemical properties. The key structural features of the inhibitors consist of a combination of a spiro[2.5]oct-6-ylmethylamine P2 group at the 4-position, a small or polar P3 group at the 5-position and/or a polar group at the 6-position of the pyrimidine.
MeSH terms
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Animals
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Cathepsins / antagonists & inhibitors*
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Chemistry, Pharmaceutical / methods*
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Cysteine Proteinase Inhibitors / chemical synthesis*
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Cysteine Proteinase Inhibitors / pharmacology
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Drug Design
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Humans
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Inhibitory Concentration 50
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Male
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Molecular Conformation
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Nitriles / chemical synthesis*
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Nitriles / pharmacology
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Peptides / chemistry*
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Pyrimidines / chemical synthesis*
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Pyrimidines / chemistry*
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Pyrimidines / pharmacology
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Rats
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Rats, Sprague-Dawley
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Recombinant Proteins / chemistry
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Structure-Activity Relationship
Substances
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Cysteine Proteinase Inhibitors
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Nitriles
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Peptides
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Pyrimidines
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Recombinant Proteins
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Cathepsins
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cathepsin S