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

• Published in: Bioorganic & medicinal chemistry letters 2016-12, Vol.26 (23), p.5695-5702
• Main Authors: Zhu, Yuping, de Jesus, Reynalda K., Tang, Haifeng, Walsh, Shawn P., Jiang, Jinlong, Gu, Xin, Teumelsan, Nardos, Shahripour, Aurash, Pio, Barbara, Ding, Fa-Xiang, Ha, Sookhee, Priest, Birgit T., Swensen, Andrew M., Alonso-Galicia, Magdalena, Felix, John P., Brochu, Richard M., Bailey, Timothy, Thomas-Fowlkes, Brande, Zhou, Xiaoyan, Pai, Lee-Yuh, Hampton, Caryn, Hernandez, Melba, Owens, Karen, Ehrhart, Juliann, Roy, Sophie, Kaczorowski, Gregory J., Yang, Lihu, Parmee, Emma R., Sullivan, Kathleen, Garcia, Maria L., Pasternak, Alexander
• Format: Article
• Language: English
• Subjects: Animals; Diuresis; Diuresis - drug effects; Dogs; Heart failure; Heart Failure - drug therapy; hERG; Humans; Hypertension; Hypertension - drug therapy; Macaca mulatta; Natriuresis; Oxazines - chemistry; Oxazines - pharmacokinetics; Oxazines - pharmacology; Potassium Channels, Inwardly Rectifying - antagonists & inhibitors; Potassium Channels, Inwardly Rectifying - metabolism; Rats, Sprague-Dawley; ROMK; Transcriptional Regulator ERG - antagonists & inhibitors; Transcriptional Regulator ERG - metabolism
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2016.10.064

[Display omitted] 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.