cortivazol

Clinical trial activity

4 trials · 4 clinical orgs · 0 marketing orgs

Earliest trial started Dec 1, 2008 (NCT00804895)

Indications

Mechanism of action

• Glucocorticoid receptorAGONIST

  NR3C1 agonist

  Structurally, cortivazol possesses the unique feature of a bulky phenylpyrazole structure fused at carbon atoms 2 and 3 to the A ring of the steroid moiety. This pyrazoloid structure imparts a significant increase in potency to the molecule and results in unusual two-site binding kinetics with the glucocorticoid receptor. Cortivazol induces the nuclear translocation and transactivation function of the glucocorticoid receptor, but not of the mineralocorticoid receptor.

  Cortivazol has high affinity for the glucocorticoid receptor (GR) (10¿20 times greater affinity for the GR than dexamethasone)

  Cortivazol binds to the glucocorticoid receptor in the cytosol from CEM C7 cells (a human acute lymphoblastic leukemia line) in a fashion consistent with interaction with at least two sites. In mutant leukemia cells derived from CEM C7, resistant to kill by 10-4 M dexamethasone and deficient in standard glucocorticoid binding sites, cortivazol still finds a binding site and kills the cells. In wild-type leukemia cells, the binding sites of cortivazol, those with both higher (Kd ~5 x 10-10 M) and lower (Kd ~1 X 10-8 M) affinity appear to be on forms of the glucocorticoid receptor itself, and not on two different classes of molecules. Cortivazol interacts with the distinct portion of the ligand binding domain (LBD) and differentially modulates the ligand-dependent interaction between transcription intermediary factor 2 and the LBD when compared with cortisol, dexamethasone and aldosterone.

  • Glucocorticoid receptor (NR3C1) ↗