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Besides its blood pressure\u2010lowering properties, the AT<jats:sub>1<\/jats:sub>\u2010receptor blocker telmisartan has been shown to be a partial agonist of PPAR\u03b3 with beneficial metabolic effects in vitro and in mice. In our previous work, comprehensive structure\u2013activity relationship (SAR) studies discussed the different parts of the telmisartan structure and various moieties. Based on these findings, we designed and synthesized new PPAR\u03b3 ligands with a benzimidazole (agonists <jats:bold>4<\/jats:bold>\u2010<jats:bold>5<\/jats:bold> and <jats:bold>4<\/jats:bold>\u2010<jats:bold>6<\/jats:bold>), benzothiophene (agonists <jats:bold>5<\/jats:bold>\u2010<jats:bold>5<\/jats:bold> and <jats:bold>5<\/jats:bold>\u2010<jats:bold>6<\/jats:bold>) or benzofuran (agonists <jats:bold>6<\/jats:bold>\u2010<jats:bold>5<\/jats:bold> and <jats:bold>6<\/jats:bold>\u2010<jats:bold>6<\/jats:bold>) moiety either at position\u20055 or\u20056 of the benzimidazole core structure. Lipophilicity and EC<jats:sub>50<\/jats:sub> values were improved for all new compounds compared with telmisartan. Regarding PPAR\u03b3 activation, the compounds were characterized by a differentiation assay using 3T3\u2010L1 cells and a luciferase assay with COS\u20107 cells transiently transfected with pGal4\u2010hPPARgDEF, pGal5\u2010TK\u2010pGL3 and pRL\u2010CMV. A decrease in both potency and efficacy was observed after the shift of either the benzothiophene or the benzofuran moiety from position\u20056 to position\u20055. Selective recruitment of the coactivators TRAP220, SRC\u20101 and PGC\u20101\u03b1, and release of corepressor NCoR1 determined by time\u2010resolved fluorescence resonance energy transfer (TR\u2010FRET) was detected depending on residues in position\u20055 or\u20056.<\/jats:p>","DOI":"10.1002\/cmdc.201200337","type":"journal-article","created":{"date-parts":[[2012,10,29]],"date-time":"2012-10-29T14:02:57Z","timestamp":1351519377000},"page":"1935-1942","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Characterization of Telmisartan\u2010Derived PPAR\u03b3 Agonists: Importance of Moiety Shift from Position\u20056 to\u20055 on Potency, Efficacy and Cofactor Recruitment"],"prefix":"10.1002","volume":"7","author":[{"given":"Lena","family":"Herbst","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthias","family":"Goebel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sebastian","family":"Bandholtz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ronald","family":"Gust","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ulrich","family":"Kintscher","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2012,10,29]]},"reference":[{"key":"e_1_2_6_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2005.11.026"},{"key":"e_1_2_6_2_2","unstructured":"\u00a0"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1517\/13543784.15.3.243"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.2337\/diacare.27.1.256"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1155\/2011\/867180"},{"key":"e_1_2_6_6_2","unstructured":"\u00a0"},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature09291"},{"key":"e_1_2_6_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature10383"},{"key":"e_1_2_6_9_2","unstructured":"\u00a0"},{"key":"e_1_2_6_10_2","doi-asserted-by":"publisher","DOI":"10.1023\/A:1005405526283"},{"key":"e_1_2_6_11_2","doi-asserted-by":"publisher","DOI":"10.2337\/dc10-1068"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.1210\/me.2002-0217"},{"key":"e_1_2_6_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/25931"},{"key":"e_1_2_6_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2007.07.014"},{"key":"e_1_2_6_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2011.10.018"},{"key":"e_1_2_6_16_2","unstructured":"\u00a0"},{"key":"e_1_2_6_17_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.0000123072.34629.57"},{"key":"e_1_2_6_18_2","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.54.12.3442"},{"key":"e_1_2_6_19_2","unstructured":"\u00a0"},{"key":"e_1_2_6_20_2","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.200800285"},{"key":"e_1_2_6_21_2","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.200900067"},{"key":"e_1_2_6_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2010.06.102"},{"key":"e_1_2_6_23_2","doi-asserted-by":"publisher","DOI":"10.1248\/cpb.53.492"},{"key":"e_1_2_6_24_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm00077a007"},{"key":"e_1_2_6_25_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm200409s"},{"key":"e_1_2_6_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2009.12.107"},{"key":"e_1_2_6_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(00)80211-7"},{"key":"e_1_2_6_28_2","unstructured":"\u00a0"},{"key":"e_1_2_6_29_2","doi-asserted-by":"publisher","DOI":"10.1002\/dmrr.1187"},{"key":"e_1_2_6_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jdiacomp.2010.06.006"},{"key":"e_1_2_6_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1278"},{"key":"e_1_2_6_32_2","doi-asserted-by":"publisher","DOI":"10.1155\/2010\/703735"},{"key":"e_1_2_6_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(01)00353-7"},{"key":"e_1_2_6_34_2","doi-asserted-by":"crossref","first-page":"2099","DOI":"10.1016\/S0022-2275(20)32433-0","volume":"40","author":"Rasp\u00e9 E.","year":"1999","journal-title":"J. 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