2. Academic Validation
  3. Development of WNK signaling inhibitors as a new class of antihypertensive drugs

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.
Mari Ishigami-Yuasa 1,  Yuko Watanabe 1,  Takayasu Mori 2,  Hiroyuki Masuno 1,  Shinya Fujii 1,  Eriko Kikuchi 2,  Shinichi Uchida 2,  Hiroyuki Kagechika 3
Affiliations

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).

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