Discovery of a clinical candidate from the structurally unique dioxa-bicyclo[3.2.1]octane class of sodium-dependent glucose cotransporter 2 inhibitors

J Med Chem. 2011 Apr 28;54(8):2952-60. doi: 10.1021/jm200049r. Epub 2011 Mar 30.


Compound 4 (PF-04971729) belongs to a new class of potent and selective sodium-dependent glucose cotransporter 2 inhibitors incorporating a unique dioxa-bicyclo[3.2.1]octane (bridged ketal) ring system. In this paper we present the design, synthesis, preclinical evaluation, and human dose predictions related to 4. This compound demonstrated robust urinary glucose excretion in rats and an excellent preclinical safety profile. It is currently in phase 2 clinical trials and is being evaluated for the treatment of type 2 diabetes.

MeSH terms

  • Animals
  • Area Under Curve
  • Bridged Bicyclo Compounds, Heterocyclic / chemistry*
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacokinetics
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
  • Crystallography, X-Ray
  • Drug Discovery*
  • Drug Evaluation, Preclinical
  • Humans
  • Magnetic Resonance Spectroscopy
  • Mass Spectrometry
  • Models, Molecular
  • Rats
  • Sodium-Glucose Transporter 2 Inhibitors*


  • Bridged Bicyclo Compounds, Heterocyclic
  • Sodium-Glucose Transporter 2 Inhibitors