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Novel ketal ligands for the glucocorticoid receptor: in vitro and in vivo activity |
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| Authors: | Smith Cameron J Ali Amjad Balkovec James M Graham Donald W Hammond Milton L Patel Gool F Rouen Gregory P Smith Scott K Tata James R Einstein Monica Ge Lan Harris Georgianna S Kelly Theresa M Mazur Paul Thompson Chris M Wang Chuanlin F Williamson Joanne M Miller Douglas K Pandit Shilpa Santoro Joseph C Sitlani Ayesha Yamin Ting-Ting D O'Neill Edward A Zaller Dennis M Carballo-Jane Ester Forrest Michael J Luell Silvi |
| Institution: | Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. cameron_smith@merck.com |
| Abstract: | A novel series of selective ligands for the human glucocorticoid receptor is described. Structure-activity studies focused on variation of B-ring size, ketal ring size, and ketal substitution. These analogs were found to be potent and selective ligands for GR and have partial agonist profiles in functional assays for transactivation (TAT, GS) and transrepression (IL-6). Of these compounds, 27, 28, and 35 were evaluated further in a mouse LPS-induced TNF-alpha secretion model. Compound 28 had an ED(50) of 14.1 mg/kg compared with 0.5 mg/kg for prednisolone in the same assay. |
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