The design and synthesis of novel spirocyclic heterocyclic sulfone ROMK inhibitors as diuretics.
作者信息
Chobanian Harry R, Guo Yan, Pio Barbara, Tang Haifeng, Teumelsan Nardos, Clements Matthew, Frie Jessica, Ferguson Ronald, Guo Zach, Thomas-Fowlkes Brande S, Felix John P, Liu Jessica, Kohler Martin, Priest Birgit, Hampton Caryn, Pai Lee-Yuh, Corona Aaron, Metzger Joseph, Tong Vincent, Joshi Elizabeth M, Xu Ling, Owens Karen, Maloney Kevin, Sullivan Kathleen, Pasternak Alexander
机构信息
Department of Medicinal Chemistry, Merck & Co. Inc., Kenilworth, NJ 07033, United States.
Department of Ion Channels, Merck & Co. Inc., Kenilworth, NJ 07033, Unites States.
出版信息
Bioorg Med Chem Lett. 2017 Feb 15;27(4):1109-1114. doi: 10.1016/j.bmcl.2016.10.032. Epub 2016 Oct 13.
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.
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