Discovery of potent and selective GIRK1/2 modulators via 'molecular switches' within a series of 1-(3-cyclopropyl-1-phenyl-1H-pyrazol-5-yl)ureas

Wandong Wen; Wenjun Wu; C David Weaver; Craig W Lindsley

doi:10.1016/j.bmcl.2014.08.061

Discovery of potent and selective GIRK1/2 modulators via 'molecular switches' within a series of 1-(3-cyclopropyl-1-phenyl-1H-pyrazol-5-yl)ureas

Bioorg Med Chem Lett. 2014 Nov 1;24(21):5102-6. doi: 10.1016/j.bmcl.2014.08.061. Epub 2014 Sep 16.

Authors

Wandong Wen¹, Wenjun Wu², C David Weaver³, Craig W Lindsley⁴

Affiliations

¹ College of Science, Northwest A&F University, Yangling, Shaanxi 712100, China; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
² College of Science, Northwest A&F University, Yangling, Shaanxi 712100, China. Electronic address: wuwenjun@nwsuaf.edu.cn.
³ Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University/Vanderbilt University Medical Center, Nashville, TN 37232, USA.
⁴ Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University/Vanderbilt University Medical Center, Nashville, TN 37232, USA. Electronic address: craig.lindsley@vanderbilt.edu.

PMID: 25264075
DOI: 10.1016/j.bmcl.2014.08.061

Abstract

This Letter describes the on-going SAR efforts based on ML297, a potent, efficacious and selective GIRK1/2 activator (∼ 10-fold vs GIRK1/4 and inactive on GIRK2/3) via an iterative parallel synthesis approach. The chemical optimization at the 3-position of pyrazole within ML297 indicated that various functionalized 3-cyclopropyl moieties modulated GIRK pharmacology between inhibitor/activator within a series of 1-(3-cyclopropyl-1-phenyl-1H-pyrazol-5-yl)ureas. Importantly, novel 'molecular switches' that modulated the mode of pharmacology from inhibitor to activator was discovered on both the 3-cyclopropyl and N-phenyl moiety of the pyrazole core, providing the first highly selective GIRK1/2 activator.

Keywords: Activators; GIRK; Inhibitors; K(ir)3.x; Thallium flux.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Drug Evaluation, Preclinical
G Protein-Coupled Inwardly-Rectifying Potassium Channels / agonists
G Protein-Coupled Inwardly-Rectifying Potassium Channels / antagonists & inhibitors
G Protein-Coupled Inwardly-Rectifying Potassium Channels / metabolism*
Microsomes / metabolism
Phenylurea Compounds / chemistry
Protein Binding
Pyrazoles / chemistry*
Rats
Structure-Activity Relationship
Urea / chemistry*
Urea / metabolism

Substances

CID 56642816
G Protein-Coupled Inwardly-Rectifying Potassium Channels
Phenylurea Compounds
Pyrazoles
pyrazole
Urea

Grants and funding

U54MH084659/MH/NIMH NIH HHS/United States