Abstract
A pharmacophore model of the P1' site, specific for aggrecanase, was defined using the specificity studies of the matrix metalloproteinases and the similar biological activity of aggrecanase and MMP-8. Incorporation of the side chain of a tyrosine residue into compound 1 as the P1' group provided modest selectivity for aggrecanase over MMP-1, -2, and -9. A cis-(1S)(2R)-amino-2-indanol scaffold was incorporated as a tyrosine mimic (P2') to conformationally constrain 2. Further optimization resulted in compound 11, a potent, selective, and orally bioavailable inhibitor of aggrecanase.
MeSH terms
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Administration, Oral
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Animals
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Asparagine / analogs & derivatives
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Asparagine / chemical synthesis*
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Asparagine / chemistry
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Asparagine / pharmacokinetics
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Asparagine / pharmacology
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Biological Availability
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Dogs
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Drug Design
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Endopeptidases / chemistry
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Endopeptidases / metabolism*
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Hydroxamic Acids / chemical synthesis*
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Hydroxamic Acids / chemistry
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Hydroxamic Acids / pharmacokinetics
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Hydroxamic Acids / pharmacology
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Matrix Metalloproteinase 1 / chemistry
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Matrix Metalloproteinase 2 / chemistry
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Matrix Metalloproteinase 8 / chemistry
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Matrix Metalloproteinase 9 / chemistry
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Models, Molecular
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Protease Inhibitors / chemical synthesis*
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Protease Inhibitors / chemistry
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Protease Inhibitors / pharmacokinetics
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Protease Inhibitors / pharmacology
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Protein Binding
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Stereoisomerism
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Structure-Activity Relationship
Substances
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Hydroxamic Acids
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N-hydroxy-2-(cyclopropylmethylamino)-4-((2-hydroxyindan-1-yl)amino)-3-((3-hydroxyphenyl)methyl)-4-oxobutanamide
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Protease Inhibitors
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Asparagine
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Endopeptidases
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Matrix Metalloproteinase 2
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Matrix Metalloproteinase 8
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Matrix Metalloproteinase 9
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Matrix Metalloproteinase 1
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aggrecanase