Abstract
Rational structure-based design has yielded highly potent inhibitors of cathepsin K (Cat K) with excellent physical properties, selectivity profiles, and pharmacokinetics. Compounds with a 3,4-(CH₃O)₂Ph motif, such as 31, were found to have excellent metabolic stability and absorption profiles. Through metabolite identification studies, a reactive metabolite risk was identified with this motif. Subsequent structure-based design of isoteres culminated in the discovery of an optimized and balanced inhibitor (indazole, 38).
MeSH terms
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Animals
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Blood Proteins / metabolism
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Cathepsin K / antagonists & inhibitors*
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Cells, Cultured
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Cyclohexanes / chemical synthesis*
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Cyclohexanes / pharmacokinetics
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Cyclohexanes / pharmacology
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Drug Design
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Hepatocytes / metabolism
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Humans
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Indazoles / chemical synthesis*
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Indazoles / pharmacokinetics
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Indazoles / pharmacology
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Male
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Models, Molecular
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Protein Binding
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Rats
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Rats, Wistar
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Stereoisomerism
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Structure-Activity Relationship
Substances
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Blood Proteins
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Cyclohexanes
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Indazoles
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N-(1-cyanocyclopropyl)-2-((4-(1,3-dimethyl-1H-indazol-5-yl)-2-methylpiperazin-1-yl)carbonyl)cyclohexanecarboxamide
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Cathepsin K