Abstract
Piperidine ether and aryl piperazine hydantoins are reported as potent inhibitors of MMP13. A medicinal chemistry campaign focused on replacing the reverse hydroxamate zinc binding group associated with historical inhibitors with a hydantoin zinc binding group then optimising MMP13 potency, solubility and DMPK properties whilst maintaining good selectivity over MMP14. A number of high quality candidates were progressed and following rat and dog safety evaluation, AZD6605 (3m) was identified as a candidate drug.
Keywords:
Cyp P450; Hydantoin; Lead optimisation; MMP13; Zinc binder.
Copyright © 2013 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Catalytic Domain
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Crystallography, X-Ray
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Dogs
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Drug Discovery*
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Enzyme Activation / drug effects
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Hydantoins / chemical synthesis*
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Hydantoins / chemistry
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Hydantoins / pharmacology*
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Inhibitory Concentration 50
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Matrix Metalloproteinase 13 / metabolism*
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Matrix Metalloproteinase Inhibitors / chemical synthesis*
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Matrix Metalloproteinase Inhibitors / chemistry
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Matrix Metalloproteinase Inhibitors / pharmacology*
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Models, Molecular
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Rats
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Solubility
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Sulfonamides / chemical synthesis*
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Sulfonamides / chemistry
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Sulfonamides / pharmacology*
Substances
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AZD6605
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Hydantoins
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Matrix Metalloproteinase Inhibitors
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Sulfonamides
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Matrix Metalloproteinase 13