| Literature DB >> 18038970 |
Keith Biggadike1, Mohamed Boudjelal, Margaret Clackers, Diane M Coe, Derek A Demaine, George W Hardy, Davina Humphreys, Graham G A Inglis, Michael J Johnston, Haydn T Jones, David House, Richard Loiseau, Deborah Needham, Philip A Skone, Iain Uings, Gemma Veitch, Gordon G Weingarten, Iain M McLay, Simon J F Macdonald.
Abstract
The synthesis and biological activity of tetrahydronaphthalene derivatives coupled to various heterocycles are described. These compounds are potent glucocorticoid receptor agonists with efficacy selectivity in an NFkappaB glucocorticoid receptor (GR) agonist assay (representing transrepression effects) over an MMTV GR agonist assay (representing transactivation effects). Quinolones, indoles, and C- and N-linked quinolines are some of the heterocycles that provide efficacy selectivity. For example, the isoquinoline 49D1E2 has NFkappaB agonism with pIC50 of 8.66 (89%) and reduced efficacy in MMTV agonism (6%), and the quinoline 55D1E1 has NFkappaB agonism with pIC50 of 9.30 (101%) and reduced efficacy in MMTV agonism with pEC50 of 8.02 (47%). A description of how a compound from each class is modeled in the active site of the receptor is given.Entities:
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Year: 2007 PMID： 18038970 DOI： 10.1021/jm070778w
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446