{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T08:40:55Z","timestamp":1793090455460,"version":"4.5.0"},"reference-count":70,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2019,11,12]],"date-time":"2019-11-12T00:00:00Z","timestamp":1573516800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Peptide Science"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:p>We discovered the orally active thyrotropin\u2010releasing hormone (TRH) mimetic: (4<jats:italic>S<\/jats:italic>,5<jats:italic>S<\/jats:italic>)\u20105\u2010methyl\u2010<jats:italic>N<\/jats:italic>\u2010{(2<jats:italic>S<\/jats:italic>)\u20101\u2010[(2<jats:italic>R<\/jats:italic>)\u20102\u2010methylpyrrolidin\u20101\u2010yl]\u20101\u2010oxo\u20103\u2010(1,3\u2010thiazol\u20104\u2010yl)propan\u20102\u2010yl}\u20102\u2010oxo\u20101,3\u2010oxazolidine\u20104\u2010carboxamide <jats:bold>1<\/jats:bold> (rovatirelin). The central nervous system (CNS) effect of rovatirelin after intravenous (iv) administration is 100\u2010fold higher than that of TRH. As <jats:bold>1<\/jats:bold> has four asymmetric carbons in its molecule, there are 16 stereoisomers. We synthesized and evaluated the anti\u2010hypothermic effect of all stereoisomers of <jats:bold>1<\/jats:bold>, which has the (4<jats:italic>S<\/jats:italic>),(5<jats:italic>S<\/jats:italic>),(2<jats:italic>S<\/jats:italic>),(2<jats:italic>R<\/jats:italic>) configuration from the N\u2010terminus to the C\u2010terminus, in order to clarify the structure\u2212activity relationship (SAR) of stereoisomers. The (4<jats:italic>R<\/jats:italic>),(5<jats:italic>R<\/jats:italic>),(2<jats:italic>R<\/jats:italic>),(2<jats:italic>S<\/jats:italic>)\u2010isomer <jats:bold>16<\/jats:bold> did not show any anti\u2010hypothermic effect. Only the (4<jats:italic>S<\/jats:italic>),(5<jats:italic>S<\/jats:italic>),(2<jats:italic>S<\/jats:italic>),(2<jats:italic>S<\/jats:italic>)\u2010isomer <jats:bold>10<\/jats:bold>, which has the (2<jats:italic>S<\/jats:italic>)\u20102\u2010methylpyrrolidine moiety at the C\u2010terminus showed the anti\u2010hypothermic effect similar to <jats:bold>1<\/jats:bold>. Stereoisomers, which have the (5<jats:italic>R<\/jats:italic>) configuration of the oxazolidinone at the N\u2010terminus and the (2<jats:italic>R<\/jats:italic>) configuration at the middle\u2010part, showed a much lower anti\u2010hypothermic effect than that of <jats:bold>1<\/jats:bold>. On the other hand, stereoisomers, which have the (4<jats:italic>R<\/jats:italic>) configuration of the oxazolidinone at the N\u2010terminus or the (2<jats:italic>S<\/jats:italic>) configuration of the C\u2010terminus, have little influence on the anti\u2010hypothermic effect.<\/jats:p>","DOI":"10.1002\/psc.3228","type":"journal-article","created":{"date-parts":[[2019,11,12]],"date-time":"2019-11-12T08:50:49Z","timestamp":1573548649000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Synthesis and evaluation of in vivo anti\u2010hypothermic effect of all stereoisomers of the thyrotropin\u2010releasing hormone mimetic: Rovatirelin Hydrate"],"prefix":"10.1002","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8631-9124","authenticated-orcid":false,"given":"Naotake","family":"Kobayashi","sequence":"first","affiliation":[{"name":"Medicinal chemistry research laboratory, Shionogi &amp; Co., Ltd. 3\u20101\u20101, Futaba\u2010cho, Toyonaka\u2010shi Osaka 561\u20100825 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norihito","family":"Sato","sequence":"additional","affiliation":[{"name":"Research Laboratory for Development, Shionogi &amp; Co., Ltd. 3\u20101\u20101, Futaba\u2010cho, Toyonaka\u2010shi Osaka 561\u20100825 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katsuji","family":"Sugita","sequence":"additional","affiliation":[{"name":"Research Laboratory for Development, Shionogi &amp; Co., Ltd. 3\u20101\u20101, Futaba\u2010cho, Toyonaka\u2010shi Osaka 561\u20100825 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kouji","family":"Takahashi","sequence":"additional","affiliation":[{"name":"DMPK Services, Shionogi Techno Advance Research Co., Ltd. 3\u20101\u20101, Futaba\u2010cho, Toyonaka\u2010shi Osaka 561\u20100825 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamio","family":"Sugawara","sequence":"additional","affiliation":[{"name":"Medicinal chemistry research laboratory, Shionogi &amp; Co., Ltd. 3\u20101\u20101, Futaba\u2010cho, Toyonaka\u2010shi Osaka 561\u20100825 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukio","family":"Tada","sequence":"additional","affiliation":[{"name":"Medicinal chemistry research laboratory, Shionogi &amp; Co., Ltd. 3\u20101\u20101, Futaba\u2010cho, Toyonaka\u2010shi Osaka 561\u20100825 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takayoshi","family":"Yoshikawa","sequence":"additional","affiliation":[{"name":"Pharmacovigilance Japan, Allergan Japan K.K., 4\u201020\u20103\u201035, Ebisu Shibuya\u2010ku Tokyo 150\u20106035 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,11,12]]},"reference":[{"key":"e_1_2_8_2_1","unstructured":"SugawaraT YoshikawaT TadaY.Novel peptide derivatives having thiazolyl\u2010alanine residue. 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