Optimization of Allosteric With-No-Lysine (WNK) Kinase Inhibitors and Efficacy in Rodent Hypertension Models

The observed structure–activity
relationship of three distinct
ATP noncompetitive With-No-Lysine (WNK) kinase inhibitor series, together
with a crystal structure of a previously disclosed allosteric inhibitor
bound to WNK1, led to an overlay hypothesis defining core and side-chain
relationships across the different series. This in turn enabled an
efficient optimization through scaffold morphing, resulting in compounds
with a good balance of selectivity, cellular potency, and pharmacokinetic
profile, which were suitable for in vivo proof-of-concept
studies. When dosed orally, the optimized compound reduced blood pressure
in mice overexpressing human WNK1, and induced diuresis, natriuresis
and kaliuresis in spontaneously hypertensive rats (SHR), confirming
that this mechanism of inhibition of WNK kinase activity is effective
at regulating cardiovascular homeostasis.