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The design and synthesis of novel spirocyclic heterocyclic sulfone ROMK inhibitors as diuretics |
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| Authors: | Harry R Chobanian Yan Guo Barbara Pio Haifeng Tang Nardos Teumelsan Matthew Clements Jessica Frie Ronald Ferguson Zach Guo Brande S Thomas-Fowlkes John P Felix Jessica Liu Martin Kohler Birgit Priest Caryn Hampton Lee-Yuh Pai Aaron Corona Joseph Metzger Alexander Pasternak |
| Institution: | 1. Department of Medicinal Chemistry, Merck & Co. Inc., Kenilworth, NJ 07033, United States;2. Department of Ion Channels, Merck & Co. Inc., Kenilworth, NJ 07033, Unites States;3. Department of Cardiometabolic Diseases, Merck & Co. Inc., Kenilworth, NJ 07033, United States;4. Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co. Inc., Kenilworth, NJ 07033, United States;5. Department of Process Chemistry, Rahway, NJ 07065, United States |
| Abstract: | 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. |
| Keywords: | ROMK Hypertension Heart Failure Heterocyclic sulfone Diuresis Natriuresis |
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