Discovery of betamethasone 17alpha-carbamates as dissociated glucocorticoid receptor modulators in the rat

Bioorg Med Chem. 2008 Aug 15;16(16):7535-42. doi: 10.1016/j.bmc.2008.07.037. Epub 2008 Jul 20.

Abstract

A series of betamethasone 17alpha-carbamates were designed, synthesized, and evaluated for their ability to dissociate the two main functions of the glucocorticoid receptor, that is, transactivation and transrepression, in rat cell lines. A number of alkyl substituted betamethasone 17alpha-carbamates were identified with excellent affinity for the glucocorticoid receptor (e.g., 7, GR IC(50) 5.1 nM) and indicated dissociated profiles in functional assays of transactivation (rat tyrosine aminotransferase, TAT, and rat glutamine synthetase, GS) and transrepression (human A549 cells, MMP-1 assay). Gratifyingly, the in-vivo profile of these compounds, for example, 7, also indicated potent anti-inflammatory activity with impaired effects on glucose, insulin, triglycerides, and body weight. Taken together, these results indicate that dissociated glucocorticoid receptor modulators can be identified in rodents.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / chemical synthesis
  • Anti-Inflammatory Agents / chemistry
  • Anti-Inflammatory Agents / pharmacokinetics
  • Anti-Inflammatory Agents / pharmacology
  • Betamethasone / analogs & derivatives*
  • Betamethasone / chemical synthesis
  • Betamethasone / pharmacokinetics
  • Betamethasone / pharmacology
  • Blood Glucose / metabolism
  • Body Weight / drug effects
  • Carbamates / chemical synthesis*
  • Carbamates / chemistry
  • Carbamates / pharmacokinetics
  • Carbamates / pharmacology
  • Glutamate-Ammonia Ligase / metabolism
  • Insulin / blood
  • Liver / drug effects
  • Liver / metabolism
  • Matrix Metalloproteinase 1 / metabolism
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism
  • Rats
  • Receptors, Glucocorticoid / chemistry
  • Receptors, Glucocorticoid / metabolism*
  • Triglycerides / blood
  • Tyrosine Transaminase / metabolism

Substances

  • Anti-Inflammatory Agents
  • Blood Glucose
  • Carbamates
  • Insulin
  • Receptors, Glucocorticoid
  • Triglycerides
  • Betamethasone
  • Tyrosine Transaminase
  • Matrix Metalloproteinase 1
  • Glutamate-Ammonia Ligase