Abstract
Directed screening of nitrile compounds revealed 3 as a highly potent cathepsin K inhibitor but with cathepsin S activity and very poor stability to microsomes. Synthesis of compounds with reduced molecular complexity, such as 7, revealed key SAR and demonstrated that baseline physical properties and in vitro stability were in fact excellent for this series. The tricycle carboline P3 unit was discovered by hypothesis-based design using existing structural information. Optimization using small substituents, knowledge from matched molecular pairs, and control of lipophilicity yielded compounds very close to the desired profile, of which 34 (AZD4996) was selected on the basis of pharmacokinetic profile.
MeSH terms
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Animals
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Carbolines / metabolism
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Carbolines / pharmacokinetics
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Carbolines / pharmacology*
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Carbolines / therapeutic use
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Cathepsin K / antagonists & inhibitors*
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Cathepsin K / chemistry
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Dogs
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Humans
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Indoles / metabolism
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Indoles / pharmacokinetics
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Indoles / pharmacology*
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Indoles / therapeutic use
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Inhibitory Concentration 50
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Male
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Models, Molecular
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Osteoarthritis / drug therapy*
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Osteoarthritis / enzymology
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Protease Inhibitors / metabolism
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Protease Inhibitors / pharmacokinetics
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Protease Inhibitors / pharmacology*
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Protease Inhibitors / therapeutic use
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Protein Conformation
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Rats
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Substrate Specificity
Substances
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Carbolines
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Indoles
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N-(1-cyanocyclopropyl)-2-(6-methoxy-1,3,4,5-tetrahydropyrido(4,3-b)indole-2-carbonyl)cyclohexanecarboxamide
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Protease Inhibitors
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Cathepsin K