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Bioorg Med Chem Lett. 2017 Feb 15;27(4):1109-1114. doi: 10.1016/j.bmcl.2016.10.032. Epub 2016 Oct 13.

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

Author information

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:

Diuresis; Heart Failure; Heterocyclic sulfone; Hypertension; Natriuresis; ROMK

PMID:
28111141
DOI:
10.1016/j.bmcl.2016.10.032
[Indexed for MEDLINE]

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