Hydantoin based inhibitors of MMP13--discovery of AZD6605

  • Bioorg Med Chem Lett. 2013 Aug 15;23(16):4705-12. doi: 10.1016/j.bmcl.2013.05.089.
Chris De Savi  1 ,  David Waterson ,  Andrew Pape ,  Scott Lamont ,  Elma Hadley ,  Mark Mills ,  Ken M Page ,  Jonathan Bowyer ,  Rose A Maciewicz
Affiliations
  • 1. Oncology Innovative Medicines, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA. [email protected]
PMID: 23810497 DOI: 10.1016/j.bmcl.2013.05.089
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.
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