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.