Development of WNK signaling inhibitors as a new class of antihypertensive drugs

Mari Ishigami-Yuasa; Yuko Watanabe; Takayasu Mori; Hiroyuki Masuno; Shinya Fujii; Eriko Kikuchi; Shinichi Uchida; Hiroyuki Kagechika

doi:10.1016/j.bmc.2017.05.034

Development of WNK signaling inhibitors as a new class of antihypertensive drugs

Bioorg Med Chem. 2017 Jul 15;25(14):3845-3852. doi: 10.1016/j.bmc.2017.05.034. Epub 2017 May 19.

Authors

Mari Ishigami-Yuasa¹, Yuko Watanabe¹, Takayasu Mori², Hiroyuki Masuno¹, Shinya Fujii¹, Eriko Kikuchi², Shinichi Uchida², Hiroyuki Kagechika³

Affiliations

¹ Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), 2-3-10 Kanda-Surugadai, Chiyodaku, Tokyo 101-0062, Japan.
² Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyoku, Tokyo 113-8519, Japan.
³ Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), 2-3-10 Kanda-Surugadai, Chiyodaku, Tokyo 101-0062, Japan. Electronic address: kage.chem@tmd.ac.jp.

PMID: 28566208
DOI: 10.1016/j.bmc.2017.05.034

Abstract

Pseudohypoaldosteronism type II (PHAII) is characterized by hyperkalemia and hypertension despite a normal glomerular filtration rate. Abnormal activation of the signal cascade of with-no-lysine kinase (WNK) with OSR1 (oxidative stress-responsive kinase 1)/SPAK (STE20/SPS1-related proline/alanine-rich kinase) and NCC (NaCl cotransporter) results in characteristic salt-sensitive hypertension. Thus, inhibitors of the WNK-OSR1/SPAK-NCC cascade are candidates for a new class of antihypertensive drugs. In this study, we developed novel inhibitors of this signal cascade from the 9-aminoacridine lead compound 1, one of the hit compounds obtained by screening our chemical library for WNK-SPAK binding inhibitors. Among the synthesized acridine derivatives, several acridine-3-amide and 3-urea derivatives, such as 10 (IC₅₀: 6.9μM), 13 (IC₅₀: 2.6μM), and 20 (IC₅₀: 4.8μM), showed more potent inhibitory activity than the lead compound 1 (IC₅₀: 15.4μM). Compounds 10 and 20 were confirmed to inhibit phosphorylation of NCC in vivo.

Keywords: Acridine; Antihypertensive drug; With-no-lysine kinase (WNK).

MeSH terms

Aminacrine / chemistry
Aminacrine / metabolism
Aminacrine / pharmacology
Animals
Antihypertensive Agents / chemistry*
Antihypertensive Agents / metabolism
Antihypertensive Agents / pharmacology
Cell Survival / drug effects
HEK293 Cells
Humans
Immunoblotting
Inhibitory Concentration 50
Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
Intracellular Signaling Peptides and Proteins / metabolism*
Kidney / drug effects
Kidney / metabolism
Mice
Mice, Inbred C57BL
Minor Histocompatibility Antigens / metabolism*
Phosphorylation / drug effects
Protein Serine-Threonine Kinases / antagonists & inhibitors
Protein Serine-Threonine Kinases / metabolism*
Signal Transduction / drug effects
Sodium-Potassium-Chloride Symporters / chemistry
Sodium-Potassium-Chloride Symporters / metabolism
Structure-Activity Relationship
WNK Lysine-Deficient Protein Kinase 1

Substances

Antihypertensive Agents
Intracellular Signaling Peptides and Proteins
Minor Histocompatibility Antigens
Sodium-Potassium-Chloride Symporters
Aminacrine
OXSR1 protein, human
Protein Serine-Threonine Kinases
STK39 protein, human
WNK Lysine-Deficient Protein Kinase 1
WNK1 protein, human