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. Epub 2013 Jun 10.

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.

MeSH terms

  • Animals
  • Catalytic Domain
  • Crystallography, X-Ray
  • Dogs
  • Drug Discovery*
  • Enzyme Activation / drug effects
  • Hydantoins / chemical synthesis*
  • Hydantoins / chemistry
  • Hydantoins / pharmacology*
  • Inhibitory Concentration 50
  • Matrix Metalloproteinase 13 / metabolism*
  • Matrix Metalloproteinase Inhibitors / chemical synthesis*
  • Matrix Metalloproteinase Inhibitors / chemistry
  • Matrix Metalloproteinase Inhibitors / pharmacology*
  • Models, Molecular
  • Rats
  • Solubility
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology*

Substances

  • AZD6605
  • Hydantoins
  • Matrix Metalloproteinase Inhibitors
  • Sulfonamides
  • Matrix Metalloproteinase 13