Format

Send to

Choose Destination
Bioorg Med Chem Lett. 2016 May 1;26(9):2339-43. doi: 10.1016/j.bmcl.2016.03.035. Epub 2016 Mar 12.

Differentiation of ROMK potency from hERG potency in the phenacetyl piperazine series through heterocycle incorporation.

Author information

1
Discovery Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, United States. Electronic address: shawn_walsh@merck.com.
2
Discovery Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
3
Department of Pharmacology, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
4
Department of Cardiometabolic Diseases, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
5
Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
6
Department of Safety Assessment and Lab Animal Research, Merck Research Laboratories, Kenilworth, NJ 07033, United States.

Abstract

Following the discovery of small molecule acyl piperazine ROMK inhibitors and their initial preclinical validation as a novel diuretic agent, our group set out to discover new ROMK inhibitors with reduced risk for QT effects, suitable for further pharmacological experiments in additional species. Several strategies for decreasing hERG affinity while maintaining ROMK inhibition were investigated and are described herein. The most promising candidate, derived from the newly discovered 4-N-heteroaryl acetyl series, improved functional hERG/ROMK ratio by >10× over the previous lead. In vivo evaluation demonstrated comparable diuretic effects in rat with no detectable QT effects at the doses evaluated in an in vivo dog model.

KEYWORDS:

Diuresis; Heart failure; Hypertension; Natriuresis; ROMK; hERG

PMID:
27017115
DOI:
10.1016/j.bmcl.2016.03.035
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center