Improvement of hERG-ROMK index of spirocyclic ROMK inhibitors through scaffold optimization and incorporation of novel pharmacophores. Issue 11 (1st June 2017)

• Record Type: Journal Article
• Authors: Dong, Shuzhi; VanGelder, Kelsey; Shi, Zhi-Cai; Yu, Yang; Wu, Zhicai; Ferguson, Ron; Guo, Zack Zhiqiang; Tang, Haifeng; Frie, Jessica; Fu, Qinghong; Gu, Xin; Priest, Birgit T.; Thomas-Fowlkes, Brande; Weinglass, Adam; Margulis, Michael; Liu, Jessica; Pai, Lee-Yuh; Hampton, Caryn; Haimbach, Robin E.; Owens, Karen; Tong, Vincent; Xu, Shiyao; Hu, Mengwei; Zingaro, Gloria J.; Morissette, Pierre; Ehrhart, Juliann; Roy, Sophie; Sullivan, Kathleen; Pasternak, Alexander
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 27:Issue 11(2017)
• Page Start: 2559
• Page End: 2566
• Publication Date: 2017-06-01
• Subjects: hERG -- ROMK -- Hypertension -- Heart failure -- Diuresis -- Natriuresis -- Spirocycle; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.03.086
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: SAR in the previously described spirocyclic ROMK inhibitor series was further evolved from lead4 by modification of the spirocyclic core and identification of novel right-side pharmacophores. In this process, it was discovered that the spiropyrrolidinone core with the carbonyl group α to the spirocenter was preferred for potent ROMK activity. Efforts aimed at decreasing hERG affinity within the series led to the discovery of multiple novel right-hand pharmacophores including 3-methoxythiadiazole, 2-methoxypyrimidine, and pyridazinone. The most promising candidate is pyridazinone analog32 that showed an improved functional hERG/ROMK potency ratio and preclinical PK profile. In vivo evaluation of32 demonstrated blood pressure lowering effects in the spontaneously hypertensive rat model.