Abstract
We describe here orally active and brain-penetrant cathepsin S selective inhibitors, which are virtually devoid of hERG K(+) channel affinity, yet exhibit nanomolar potency against cathepsin S and over 100-fold selectivity to cathepsin L. The new non-peptidic inhibitors are based on a 2-cyanopyrimidine scaffold bearing a spiro[3.5]non-6-yl-methyl amine at the 4-position. The brain-penetrating cathepsin S inhibitors demonstrate potential clinical utility for the treatment of multiple sclerosis and neuropathic pain.
MeSH terms
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Administration, Oral
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Animals
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Brain / drug effects
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Cathepsin L
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Cathepsins / antagonists & inhibitors*
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Combinatorial Chemistry Techniques
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Cysteine Endopeptidases
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Ether-A-Go-Go Potassium Channels / metabolism*
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Humans
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Male
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Molecular Structure
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Multiple Sclerosis / drug therapy
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Pain / drug therapy
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Pyrimidines / blood
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Pyrimidines / chemical synthesis*
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Pyrimidines / pharmacokinetics
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Pyrimidines / pharmacology*
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Rats
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Rats, Sprague-Dawley
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Structure-Activity Relationship
Substances
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Ether-A-Go-Go Potassium Channels
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Pyrimidines
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Cathepsins
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Cysteine Endopeptidases
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CTSL protein, human
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Cathepsin L
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Ctsl protein, rat
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cathepsin S