2-(2-Aminothiazol-4-yl)pyrrolidine-based tartrate diamides as potent, selective and orally bioavailable TACE inhibitors

Bioorg Med Chem Lett. 2011 May 15;21(10):3172-6. doi: 10.1016/j.bmcl.2011.01.002. Epub 2011 Jan 6.

Abstract

TNF-α converting enzyme (TACE) inhibitors are promising agents to treat inflammatory disorders and cancer. We have investigated novel tartrate diamide TACE inhibitors where the tartrate core binds to zinc in a unique tridentate fashion. Incorporating (R)-2-(2-N-alkylaminothiazol-4-yl)pyrrolidines into the left hand side amide of the tartrate scaffold led to the discovery of potent and selective TACE inhibitors, some of which exhibited good rat oral bioavailability.

MeSH terms

  • ADAM Proteins / antagonists & inhibitors*
  • ADAM17 Protein
  • Amides / chemical synthesis
  • Amides / chemistry
  • Amides / pharmacology*
  • Animals
  • Biological Availability
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Molecular Structure
  • Pyrrolidines / chemistry*
  • Rats
  • Tartrates / chemistry*

Substances

  • Amides
  • Enzyme Inhibitors
  • Pyrrolidines
  • Tartrates
  • ADAM Proteins
  • ADAM17 Protein
  • Adam17 protein, rat
  • tartaric acid