Hydantoin based inhibitors of MMP13--discovery of AZD6605.

Authors:
Dr. Chris De Savi, PhD
Dr. Chris De Savi, PhD
Kymera Therapeutics
Vice President of Drug Discovery
Cambridge, MA | United States

Bioorg Med Chem Lett 2013 Aug 10;23(16):4705-12. Epub 2013 Jun 10.

Oncology Innovative Medicines, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.

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.

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http://dx.doi.org/10.1016/j.bmcl.2013.05.089DOI Listing
August 2013
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