口服有效的促甲状腺激素释放激素模拟物的发现：1-{[(4,5)-(5-甲基-2-氧代恶唑烷-4-基)羰基]-3-(噻唑-4-基)-L-丙氨酰}-(2)-2-甲基吡咯烷三水合物（罗伐瑞林水合物）

Discovery of the Orally Effective Thyrotropin-Releasing Hormone Mimetic: 1-{-[(4,5)-(5-Methyl-2-oxooxazolidine-4-yl)carbonyl]-3-(thiazol-4-yl)-l-alanyl}-(2)-2-methylpyrrolidine Trihydrate (Rovatirelin Hydrate).

作者信息

Kobayashi Naotake, Sato Norihito, Fujimura Yuko, Kihara Tsuyoshi, Sugita Katsuji, Takahashi Kouji, Koike Katsumi, Sugawara Tamio, Tada Yukio, Nakai Hiroshi, Yoshikawa Takayoshi

机构信息

Medicinal Chemistry Research Laboratory, Research Laboratory for Development, and Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd., 3-1-1, Futaba-cho, Toyonaka-shi, Osaka 561-0825, Japan.

Business Search & Evaluation, Shionogi & Co., Ltd., 3-1-8, Doshomachi, Chuo-ku, Osaka-shi, Osaka 541-0045, Japan.

出版信息

ACS Omega. 2018 Oct 31;3(10):13647-13666. doi: 10.1021/acsomega.8b01481. Epub 2018 Oct 19.

We have explored orally effective thyrotropin-releasing hormone (TRH) mimetics, showing oral bioavailability and brain penetration by structure-activity relationship (SAR) study on the basis of in vivo antagonistic activity on reserpine-induced hypothermia in mice. By primary screening of the synthesized TRH mimetics, we found a novel TRH mimetic: l-pyroglutamyl-[3-(thiazol-4-yl)-l-alanyl]-l-prolinamide with a high central nervous system effect compared with TRH as a lead compound. Further SAR optimization studies of this lead compound led to discovery of a novel orally effective TRH mimetic: 1-{-[(4,5)-(5-methyl-2-oxooxazolidine-4-yl)carbonyl]-3-(thiazol-4-yl)-l-alanyl}-(2)-2-methylpyrrolidine trihydrate (rovatirelin hydrate), which was selected as a candidate for clinical trials.

我们基于对小鼠利血平诱导的体温过低的体内拮抗活性，通过构效关系（SAR）研究探索了口服有效的促甲状腺激素释放激素（TRH）模拟物，其具有口服生物利用度和脑渗透性。通过对合成的TRH模拟物进行初步筛选，我们发现了一种新型TRH模拟物：L-焦谷氨酰-[3-(噻唑-4-基)-L-丙氨酰]-L-脯氨酰胺，与作为先导化合物的TRH相比，其具有较高的中枢神经系统效应。对该先导化合物进一步的构效关系优化研究导致发现了一种新型口服有效的TRH模拟物：1-{[(4,5)-(5-甲基-2-氧代恶唑烷-4-基)羰基]-3-(噻唑-4-基)-L-丙氨酰}-(2)-2-甲基吡咯烷三水合物（罗伐替林水合物），其被选为临床试验候选药物。