2. Academic Validation
  3. Novel N-arylpyrazolo[3,2-c]-based ligands for the glucocorticoid receptor: receptor binding and in vivo activity

Novel N-arylpyrazolo[3,2-c]-based ligands for the glucocorticoid receptor: receptor binding and in vivo activity

  • J Med Chem. 2004 May 6;47(10):2441-52. doi: 10.1021/jm030585i.
Amjad Ali 1,  Christopher F Thompson,  James M Balkovec,  Donald W Graham,  Milton L Hammond,  Nazia Quraishi,  James R Tata,  Monica Einstein,  Lan Ge,  Georgianna Harris,  Terri M Kelly,  Paul Mazur,  Shilpa Pandit,  Joseph Santoro,  Ayesha Sitlani,  Chuanlin Wang,  Joanne Williamson,  Douglas K Miller,  Chris M Thompson,  Dennis M Zaller,  Michael J Forrest,  Ester Carballo-Jane,  Silvi Luell
Affiliations

Affiliation

  • 1 Departments of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, New Jersey 07065, USA. amjad_ali@merck.com
PMID: 15115388 DOI: 10.1021/jm030585i
Abstract

A novel series of selective ligands for the human Glucocorticoid Receptor (hGR) are described. Preliminary structure-activity relationships were focused on substitution at C-1 and indicated a preference for 3-, 4-, and 5-substituted aromatic and benzylic groups. The resulting analogues, e.g., 18 and 34, exhibited excellent affinity for hGR (IC(50) 1.9 nM and 2.8 nM, respectively) and an interesting partial agonist profile in functional assays of transactivation (tyrosine aminotransferase, TAT, and glutamine synthetase, GS) and transrepression (IL-6). The most potent compounds described in this study were the tertiary alcohol derivatives 21 and 25. These candidates showed highly efficacious IL-6 inhibition versus dexamethasone. The thiophenyl analogue 25 was evaluated in vivo in the mouse LPS challenge model and showed an ED(50) = 4.0 mg/kg, compared to 0.5 mg/kg for prednisolone in the same assay.

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