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We adapted the strategy of switching the antagonist function of cyano\u2010group\u2010containing THQ (CN\u2010THQ) to the agonist function and optimized CN\u2010THQ as an orally available drug candidate with suitable pharmacological and ADME profiles. Based on binding mode analyses and synthetic accessibility, we designed and synthesized a compound that possesses a <jats:italic>para<\/jats:italic>\u2010substituted aromatic ring attached through an amide linker. The long\u2010tail THQ derivative 6\u2010acetamido\u2010<jats:italic>N<\/jats:italic>\u2010(2\u2010(8\u2010cyano\u20103a,4,5,9b\u2010tetrahydro\u20103<jats:italic>H<\/jats:italic>\u2010cyclopenta[<jats:italic>c<\/jats:italic>]quinolin\u20104\u2010yl)\u20102\u2010methylpropyl)nicotinamide (<jats:bold>1\u2009d<\/jats:bold>), which bears a <jats:italic>para<\/jats:italic>\u2010acetamide\u2010substituted aromatic group, showed an appropriate in vitro biological profile, as expected. We considered that the large conformational change at Trp741 of the androgen receptor (AR) and the hydrogen bond between <jats:bold>1\u2009d<\/jats:bold> and helix\u200512 of the AR could maintain the structure of the AR in its agonist form; indeed, <jats:bold>1\u2009d<\/jats:bold> displays strong AR agonistic activity. Furthermore, <jats:bold>1\u2009d<\/jats:bold> showed an appropriate in vivo profile for use as an orally available SARM, displaying clear tissue selectivity, with a separation between its desirable osteoanabolic effect on femoral bone mineral density and its undesirable virilizing effects on the uterus and clitoral gland in a female osteoporosis model.<\/jats:p>","DOI":"10.1002\/cmdc.201300348","type":"journal-article","created":{"date-parts":[[2013,11,25]],"date-time":"2013-11-25T05:36:17Z","timestamp":1385357777000},"page":"197-206","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Lead Evaluation of Tetrahydroquinolines as Nonsteroidal Selective Androgen Receptor Modulators for the Treatment of Osteoporosis"],"prefix":"10.1002","volume":"9","author":[{"given":"Naoya","family":"Nagata","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuyuki","family":"Furuya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nao","family":"Oguro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Nishiyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kentaro","family":"Kawai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noriko","family":"Yamamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Ohyabu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiro","family":"Satsukawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Motonori","family":"Miyakawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2013,11,22]]},"reference":[{"key":"e_1_2_6_1_2","unstructured":"Osteoporosis Prevention Diagnosis and Therapy NIH Consensus Statement2000 17 1\u201336."},{"key":"e_1_2_6_2_2","first-page":"1125","volume-title":"Principles of Bone Biology","author":"Schmidt A.","year":"1999"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200105103441904"},{"key":"e_1_2_6_4_2","first-page":"222","volume":"2","author":"Rosen J.","year":"2002","journal-title":"J. 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