{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T02:11:42Z","timestamp":1787019102213,"version":"build-2736575974"},"reference-count":7,"publisher":"SAGE Publications","issue":"5","license":[{"start":{"date-parts":[[2011,8,25]],"date-time":"2011-08-25T00:00:00Z","timestamp":1314230400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Int J Toxicol"],"published-print":{"date-parts":[[2011,10]]},"abstract":"<jats:p>In the process of drug design, it is important to consider potential structural alerts that may lead to toxicosis. This work illustrates how using trifluoroethane as a part of a novel chemical entity led to cytochrome P450 \u2013 mediated N-dealkylation and the formation of trifluoroacetaldehyde, a known testicular toxicant, in exploratory safety studies in rats. Testicular toxicosis was noted microscopically in a dose-dependent manner as measured by testicular spermatocytic degeneration and necrosis and excessive intratubular cellular debris in the epididymis. This apparent toxic effect correlated well with the dose-dependent formation of trifluoroacetaldehyde, identified from in vitro rat liver microsome metabolism studies. A similar safety study performed with an N-tetrazole substitution in place of the N-trifluoroethane showed no evidence of testicular injury, implicating further the role of trifluoroacetaldehyde in the testicular lesion observed. These results highlight the relevance of early metabolic and safety testing in assessing potential structural alerts in drug design.<\/jats:p>","DOI":"10.1177\/1091581811413833","type":"journal-article","created":{"date-parts":[[2011,8,25]],"date-time":"2011-08-25T23:05:58Z","timestamp":1314313558000},"page":"546-550","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":6,"title":["Drug Design Structural Alert"],"prefix":"10.1177","volume":"30","author":[{"given":"Martin E.","family":"Dowty","sequence":"first","affiliation":[{"name":"Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Global Research and Development, Pfizer, Inc, Andover, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Hu","sequence":"additional","affiliation":[{"name":"Drug Safety Research and Development, Pfizer Global Research and Development, Pfizer, Inc., Andover, MA (HVD) and Pearl River, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengmei","family":"Hua","sequence":"additional","affiliation":[{"name":"Aerotek, Saint Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F. Barclay","family":"Shilliday","sequence":"additional","affiliation":[{"name":"MPI Research, Mattawan, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather V.","family":"Dowty","sequence":"additional","affiliation":[{"name":"Drug Safety Research and Development, Pfizer Global Research and Development, Pfizer, Inc., Andover, MA (HVD) and Pearl River, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2011,8,25]]},"reference":[{"key":"bibr1-1091581811413833","doi-asserted-by":"publisher","DOI":"10.2174\/1389200054021799"},{"key":"bibr2-1091581811413833","doi-asserted-by":"publisher","DOI":"10.1080\/10408440590935620"},{"key":"bibr3-1091581811413833","doi-asserted-by":"publisher","DOI":"10.1016\/0278-6915(86)90151-1"},{"key":"bibr4-1091581811413833","doi-asserted-by":"publisher","DOI":"10.1016\/0041-008X(88)90179-2"},{"key":"bibr5-1091581811413833","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(92)90078-W"},{"key":"bibr6-1091581811413833","doi-asserted-by":"publisher","DOI":"10.1016\/0272-0590(85)90063-6"},{"issue":"11","key":"bibr7-1091581811413833","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1016\/S0090-9556(24)14938-0","volume":"27","author":"Obach RS","year":"1999","journal-title":"Drug Metabo Disposition"}],"container-title":["International Journal of Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/1091581811413833","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1177\/1091581811413833","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/1091581811413833","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T10:23:47Z","timestamp":1777458227000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/1091581811413833"}},"subtitle":["Formation of Trifluoroacetaldehyde Through\n                    <i>N<\/i>\n                    -Dealkylation is Linked to Testicular Lesions in Rat"],"short-title":[],"issued":{"date-parts":[[2011,8,25]]},"references-count":7,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2011,10]]}},"alternative-id":["10.1177\/1091581811413833"],"URL":"https:\/\/doi.org\/10.1177\/1091581811413833","relation":{},"ISSN":["1091-5818","1092-874X"],"issn-type":[{"value":"1091-5818","type":"print"},{"value":"1092-874X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,8,25]]}}}