Development of a prodrug of hydantoin based TACE inhibitor

Bioorg Med Chem Lett. 2017 Aug 15;27(16):3704-3708. doi: 10.1016/j.bmcl.2017.07.007. Epub 2017 Jul 3.

Abstract

Our research on hydantoin based TNF-α converting enzyme (TACE) inhibitors led to fused bi-heteroaryl hydantoin series that demonstrate sub-nanomolar potency (Ki) as well as excellent activity in human whole blood (hWBA). However, lead compound 2 posed some formulation challenges which prevented it for further development. A prodrug approach was investigated to address this issue. The pivalate prodrug 3 can be formulated as stable neutral form and demonstrated improved DMPK properties when compared with parent compound.

Keywords: Anti-inflammatory agent; Hydantoin; Prodrug; TACE inhibitors.

MeSH terms

  • ADAM17 Protein / antagonists & inhibitors*
  • ADAM17 Protein / metabolism
  • Administration, Oral
  • Animals
  • Area Under Curve
  • Dogs
  • Enzyme Activation / drug effects
  • Half-Life
  • Haplorhini
  • Humans
  • Hydantoins / administration & dosage
  • Hydantoins / chemical synthesis*
  • Hydantoins / chemistry*
  • Hydantoins / pharmacokinetics
  • Hydantoins / pharmacology*
  • Pentanoic Acids / administration & dosage
  • Pentanoic Acids / chemistry*
  • Pentanoic Acids / pharmacokinetics
  • Prodrugs / administration & dosage
  • Prodrugs / chemical synthesis*
  • Prodrugs / pharmacokinetics
  • Prodrugs / pharmacology*
  • ROC Curve
  • Rats
  • Structure-Activity Relationship

Substances

  • Hydantoins
  • Pentanoic Acids
  • Prodrugs
  • pivalic acid
  • ADAM17 Protein