Novartis optimizes WNK1 inhibitor hypertension candidate

In a paper published in the Journal of Medicinal Chemistry, researchers from Novartis Institutes of Biomedical Research at Novartis AG (NYSE:NVS; SIX:NOVN) identified an allosteric WNK lysine deficient protein kinase 1 (WNK1; PPP1R167) inhibitor that reduced blood pressure in hypertensive rodent models, suggesting it could help treat hypertension.

The team had previously developed three pan-WNK inhibitors that demonstrated allosteric inhibition via ATP noncompetitive inhibition. Structural analysis led to optimization of a WNK1-specific inhibitor by exchanging substituents and core motifs across the scaffolds. In vitro, the compound showed high selectivity for WNK1 and low off-target kinase inhibition, and an analog had lower clearance and two-fold greater oral bioavailability in rats than its precursor...