The design and synthesis of novel spirocyclic heterocyclic sulfone ROMK inhibitors as diuretics

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• 作者：Harry R. Chobanian^a ; ; Yan Guo^a ; Barbara Pio^a ; Haifeng Tang^a ; Nardos Teumelsan^a ; Matthew Clements^a ; Jessica Frie^a ; Ronald Ferguson^a ; Zach Guo^a ; Brande S. Thomas-Fowlkes^b ; John P. Felix^b ; Jessica Liu^b ; Martin Kohler^b ; Birgit Priest^b ; Caryn Hampton^c ; Lee-Yuh Pai^c ; Aaron Corona^c ; Joseph Metzger^c ; Vincent Tong^d ; Elizabeth M. Joshi^d ; Ling Xu^d ; Karen Owens^d ; Kevin Maloney^e ; Kathleen Sullivan^c ; Alexander Pasternak^a
• 关键词：ROMK ; Hypertension ; Heart Failure ; Heterocyclic sulfone ; Diuresis ; Natriuresis
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2017
• 出版时间：15 February 2017
• 年：2017
• 卷：27
• 期：4
• 页码：1109-1114
• 全文大小：1677 K
• 卷排序：27

文摘

A spirocyclic class of ROMK inhibitors was developed containing a structurally diverse heterocyclic sulfone moiety and spirocyclic core starting from lead 1. These compounds not only displayed exquisite ROMK potency but significantly improved selectivity over hERG. The lead compounds were found to have favorable pharmacokinetic properties and displayed robust diuretic, natriuretic and blood pressure lowering effects in spontaneously hypertensive rats.