Discovery of potent, selective and orally bioavailable triaryl-sulfonamide based PTP1B inhibitors

Bioorg Med Chem Lett. 2012 Jan 15;22(2):1111-7. doi: 10.1016/j.bmcl.2011.11.122. Epub 2011 Dec 6.

Abstract

A novel series of pTyr mimetics containing triaryl-sulfonamide derivatives (5a-r) are reported as potent and selective PTP1B inhibitors. Some of the test compounds (5o and 5p) showed excellent selectivity towards PTP1B over various PTPs, including TCPTP (in vitro). The lead compound 5o showed potent antidiabetic activity (in vivo), along with improved pharmacokinetic profile. These preliminary results confirm discovery of highly potent and selective PTP1B inhibitors for the treatment of T2DM.

MeSH terms

  • Administration, Oral
  • Animals
  • Biological Availability
  • Diabetes Mellitus / drug therapy*
  • Drug Discovery*
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / chemistry
  • Hypoglycemic Agents / pharmacology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Models, Molecular
  • Molecular Structure
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / antagonists & inhibitors*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism
  • Structure-Activity Relationship
  • Sulfonamides / administration & dosage
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology*

Substances

  • Enzyme Inhibitors
  • Hypoglycemic Agents
  • Sulfonamides
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Ptpn1 protein, mouse