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A small structural change\u2014replacing the 3,5\u2010dimethyl groups of sobetirome with either chlorine or bromine\u2014produces significantly more potent compounds, both in\u2005vitro and in\u2005vivo. These halogenated compounds induce transactivation of a TR\u03b2\u2010mediated cell\u2010based reporter with an EC<jats:sub>50<\/jats:sub> value comparable to that of T3, access the central nervous system (CNS) at levels similar to their parent, and activate an endogenous TR\u2010regulated gene in the brain with an EC<jats:sub>50<\/jats:sub> value roughly five\u2010fold lower than that of sobetirome. Previous studies suggest that this apparent increase in affinity can be explained by halogen bonding between the ligand and a backbone carbonyl group in the receptor. This makes the new analogues potential candidates for treating CNS disorders that may respond favorably to thyroid\u2010hormone\u2010stimulated pathways.<\/jats:p>","DOI":"10.1002\/cmdc.201600408","type":"journal-article","created":{"date-parts":[[2016,10,13]],"date-time":"2016-10-13T16:25:37Z","timestamp":1476375937000},"page":"2459-2465","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Increasing Thyromimetic Potency through Halogen Substitution"],"prefix":"10.1002","volume":"11","author":[{"given":"Jordan","family":"Devereaux","sequence":"first","affiliation":[{"name":"Department of Physiology &amp; Pharmacology Program in Chemical Biology Oregon Health &amp; Sciences University  3181 SW Sam Jackson Park Road Portland OR 97239 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Skylar J.","family":"Ferrara","sequence":"additional","affiliation":[{"name":"Department of Physiology &amp; Pharmacology Program in Chemical Biology Oregon Health &amp; Sciences University  3181 SW Sam Jackson Park Road Portland OR 97239 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tania","family":"Banerji","sequence":"additional","affiliation":[{"name":"Department of Physiology &amp; Pharmacology Program in Chemical Biology Oregon Health &amp; Sciences University  3181 SW Sam Jackson Park Road Portland OR 97239 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew T.","family":"Placzek","sequence":"additional","affiliation":[{"name":"Department of Physiology &amp; Pharmacology Program in Chemical Biology Oregon Health &amp; Sciences University  3181 SW Sam Jackson Park Road Portland OR 97239 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas S.","family":"Scanlan","sequence":"additional","affiliation":[{"name":"Department of Physiology &amp; Pharmacology Program in Chemical Biology Oregon Health &amp; Sciences University  3181 SW Sam Jackson Park Road Portland OR 97239 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2016,10,12]]},"reference":[{"key":"e_1_2_6_1_1","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/j.brainresrev.2004.12.022","volume":"48","author":"Calz\u00e0 L.","year":"2005","journal-title":"Brain Res. 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