Abstract
A novel series of cathepsin K inhibitors derived from Novartis compound I is described. Optimization of the P1, P3, and P1' units led to the identification of 4-aminophenoxyacetic acid 24b with an IC(50) value of 4.8 nM, which possessed an excellent selectivity over other human cathepsins and good pharmacokinetic (PK) properties. Oral administration of compound 24b to ovariectomized (OVX) rats showed a trend toward an improvement of bone mineral density (BMD) in the femur bone.
MeSH terms
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Administration, Oral
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Amines / administration & dosage
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Amines / chemistry
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Amines / pharmacology*
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Animals
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Bone Density / drug effects
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Cathepsin B / antagonists & inhibitors
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Cathepsin K
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Cathepsin L
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Cathepsins / antagonists & inhibitors*
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Cysteine Endopeptidases
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Enzyme Activation / drug effects
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Enzyme Inhibitors / administration & dosage
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Humans
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Liver / metabolism
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Microsomes / metabolism
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Molecular Conformation
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Ovariectomy
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Rats
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Recombinant Proteins / antagonists & inhibitors
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Stereoisomerism
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Structure-Activity Relationship
Substances
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Amines
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Enzyme Inhibitors
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Recombinant Proteins
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Cathepsins
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Cysteine Endopeptidases
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Cathepsin B
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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
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CTSK protein, human
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Cathepsin K
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Ctsk protein, rat