Discovery of a potent and selective ROMK inhibitor with improved pharmacokinetic properties based on an octahydropyrazino[2,1-c][1,4]oxazine scaffold

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• 作者：Yuping Zhu^a ; ^{yuping_zhu@merck.com" class="auth_mail" title="E-mail the corresponding author} ; Reynalda K. de Jesus^a ; Haifeng Tang^a ; Shawn P. Walsh^a ; Jinlong Jiang^a ; Xin Gu^a ; Nardos Teumelsan^a ; Aurash Shahripour^a ; Barbara Pio^a ; Fa-Xiang Ding^a ; Sookhee Ha^a ; Birgit T. Priest^b ; Andrew M. Swensen^b ; Magdalena Alonso-Galicia^b ; John P. Felix^b ; Richard M. Brochu^b ; Timothy Bailey^b ; Brande Thomas-Fowlkes^b ; Xiaoyan Zhou^c ; Lee-Yuh Pai^c ; Caryn Hampton^c ; Melba Hernandez^c ; Karen Owens^d ; Juliann Ehrhart^e ; Sophie Roy^c ; Gregory J. Kaczorowski^b ; Lihu Yang^a ; Emma R. Parmee^a ; Kathleen Sullivan^b ; Maria L. Garcia^b ; Alexander Pasternak^a
• 关键词：hERG ; ROMK ; Hypertension ; Heart failure ; Diuresis ; Natriuresis
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：1 December 2016
• 年：2016
• 卷：26
• 期：23
• 页码：5695-5702
• 全文大小：3460 K

文摘

Following the discovery of small molecule acyl piperazine ROMK inhibitors, the acyl octahydropyrazino[2,1-c][1,4]oxazine series was identified. This series displays improved ROMK/hERG selectivity, and as a consequence, the resulting ROMK inhibitors do not evoke QTc prolongation in an in vivo cardiovascular dog model. Further efforts in this series led to the discovery of analogs with improved pharmacokinetic profiles. This new series also retained comparable ROMK potency compared to earlier leads.