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Discovery of a novel series of 6-azauracil-based thyroid hormone receptor ligands: potent,TR beta subtype-selective thyromimetics |
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| Authors: | Dow Robert L Schneider Steven R Paight Ernest S Hank Richard F Chiang Phoebe Cornelius Peter Lee Eunsun Newsome William P Swick Andrew G Spitzer Josephine Hargrove Diane M Patterson Terrell A Pandit Jayvardhan Chrunyk Boris A LeMotte Peter K Danley Dennis E Rosner Michele H Ammirati Mark J Simons Samuel P Schulte Gayle K Tate Bonnie F DaSilva-Jardine Paul |
| Institution: | Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Groton, CT 06340, USA. robert_l_dow@groton.pfizer.com |
| Abstract: | In this communication, we wish to describe the discovery of a novel series of 6-azauracil-based thyromimetics that possess up to 100-fold selectivities for binding and functional activation of the beta(1)-isoform of the thyroid receptor family. Structure-activity relationship studies on the 3,5- and 3'-positions provided compounds with enhanced TR beta affinity and selectivity. Key binding interactions between the 6-azauracil moiety and the receptor have been determined through of X-ray crystallographic analysis. |
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