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

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; Vincent Tong; Elizabeth M Joshi; Ling Xu; Karen Owens; Kevin Maloney; Kathleen Sullivan; Alexander Pasternak

doi:10.1016/j.bmcl.2016.10.032

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

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

Authors

Harry R Chobanian¹, Yan Guo¹, Barbara Pio¹, Haifeng Tang¹, Nardos Teumelsan¹, Matthew Clements¹, Jessica Frie¹, Ronald Ferguson¹, Zach Guo¹, Brande S Thomas-Fowlkes², John P Felix², Jessica Liu², Martin Kohler², Birgit Priest², Caryn Hampton³, Lee-Yuh Pai³, Aaron Corona³, Joseph Metzger³, Vincent Tong⁴, Elizabeth M Joshi⁴, Ling Xu⁴, Karen Owens⁴, Kevin Maloney⁵, Kathleen Sullivan³, Alexander Pasternak¹

Affiliations

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.

PMID: 28111141
DOI: 10.1016/j.bmcl.2016.10.032

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.

MeSH terms

Animals
Diuretics / pharmacology*
Drug Design*
Enzyme Inhibitors / pharmacology*
Heterocyclic Compounds / chemical synthesis
Heterocyclic Compounds / chemistry*
Heterocyclic Compounds / pharmacology*
Potassium Channels, Inwardly Rectifying / antagonists & inhibitors*
Rats
Rats, Inbred SHR
Sulfones / pharmacology*

Substances

Diuretics
Enzyme Inhibitors
Heterocyclic Compounds
Kcnj1 protein, rat
Potassium Channels, Inwardly Rectifying
Sulfones