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

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.