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Bioorg Med Chem Lett. 2013 Aug 15;23(16):4705-12. doi: 10.1016/j.bmcl.2013.05.089. Epub 2013 Jun 10.

Hydantoin based inhibitors of MMP13--discovery of AZD6605.

Author information

1
Oncology Innovative Medicines, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA. chris.desavi2@astrazeneca.com

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

PMID:
23810497
DOI:
10.1016/j.bmcl.2013.05.089
[Indexed for MEDLINE]

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