401. Hydantoin based inhibitors of MMP13--discovery of AZD6605.
- Author
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De Savi C, Waterson D, Pape A, Lamont S, Hadley E, Mills M, Page KM, Bowyer J, and Maciewicz RA
- Subjects
- Animals, Catalytic Domain, Crystallography, X-Ray, Dogs, Enzyme Activation drug effects, Hydantoins chemistry, Inhibitory Concentration 50, Matrix Metalloproteinase Inhibitors chemistry, Models, Molecular, Rats, Solubility, Sulfonamides chemistry, Drug Discovery, Hydantoins chemical synthesis, Hydantoins pharmacology, Matrix Metalloproteinase 13 metabolism, Matrix Metalloproteinase Inhibitors chemical synthesis, Matrix Metalloproteinase Inhibitors pharmacology, Sulfonamides chemical synthesis, Sulfonamides pharmacology
- 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., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2013
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