Abstract
Several structure-guided optimisation strategies were explored in order to improve the hERG selectivity profile of cathepsin K inhibitor 1, whilst maintaining its otherwise excellent in vitro and in vivo profile. Ultimately, attenuation of clogP and pK(a) properties proved a successful approach and led to the discovery of a potent analogue 23, which, in addition to the desired selectivity over hERG (>1000-fold), displayed a highly attractive overall profile.
Copyright © 2010 Elsevier Ltd. All rights reserved.
MeSH terms
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Cathepsin K / antagonists & inhibitors*
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Drug Design
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Drug Discovery
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Ether-A-Go-Go Potassium Channels / drug effects*
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Indicators and Reagents
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Models, Molecular
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Nitriles / chemical synthesis*
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Nitriles / pharmacology*
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Potassium Channel Blockers / chemical synthesis*
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Potassium Channel Blockers / pharmacology*
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Pyrimidines / chemical synthesis*
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Pyrimidines / pharmacology*
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ROC Curve
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Structure-Activity Relationship
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Torsades de Pointes / drug therapy
Substances
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Ether-A-Go-Go Potassium Channels
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Indicators and Reagents
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Nitriles
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Potassium Channel Blockers
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Pyrimidines
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Cathepsin K