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

Abstract：

: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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Yamada K,Levell J,Yoon T,Kohls D,Yowe D,Rigel DF,Imase H,Yuan J,Yasoshima K,DiPetrillo K,Monovich L,Xu L,Zhu M,Kato M,Jain M,Idamakanti N,Taslimi P,Kawanami T,Argikar UA,Kunjathoor V,Xie X,Yagi YI,Iwaki Y,Ro

doi

10.1021/acs.jmedchem.7b00708

subject

Has Abstract

pub_date

2017-08-24 00:00:00

pages

7099-7107

issue

16

eissn

0022-2623

issn

1520-4804

journal_volume

60

pub_type

杂志文章

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