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

Ken Yamada; Julian Levell; Taeyong Yoon; Darcy Kohls; David Yowe; Dean F Rigel; Hidetomo Imase; Jun Yuan; Kayo Yasoshima; Keith DiPetrillo; Lauren Monovich; Lingfei Xu; Meicheng Zhu; Mitsunori Kato; Monish Jain; Neeraja Idamakanti; Paul Taslimi; Toshio Kawanami; Upendra A Argikar; Vidya Kunjathoor; Xiaoling Xie; Yukiko I Yagi; Yuki Iwaki; Zachary Robinson; Hyi-Man Park

doi:10.1021/acs.jmedchem.7b00708

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

J Med Chem. 2017 Aug 24;60(16):7099-7107. doi: 10.1021/acs.jmedchem.7b00708. Epub 2017 Aug 3.

Authors

Ken Yamada^{1

2}, Julian Levell¹, Taeyong Yoon¹, Darcy Kohls¹, David Yowe¹, Dean F Rigel³, Hidetomo Imase¹, Jun Yuan¹, Kayo Yasoshima^{1

2}, Keith DiPetrillo³, Lauren Monovich¹, Lingfei Xu³, Meicheng Zhu¹, Mitsunori Kato^{1

2}, Monish Jain¹, Neeraja Idamakanti¹, Paul Taslimi¹, Toshio Kawanami^{1

2}, Upendra A Argikar¹, Vidya Kunjathoor¹, Xiaoling Xie¹, Yukiko I Yagi², Yuki Iwaki¹, Zachary Robinson¹, Hyi-Man Park^{1

2}

Affiliations

¹ Novartis Institutes for BioMedical Research, Inc. , Cambridge, Massachusetts 02139-4133, United States.
² Novartis Institutes for BioMedical Research, Novartis Pharma K.K. , Tsukuba, Ibaraki 300-2611, Japan.
³ Novartis Institutes for BioMedical Research, Novartis Pharmaceuticals Corporation , East Hanover, New Jersey 07936-1080, United States.

PMID: 28771350
DOI: 10.1021/acs.jmedchem.7b00708

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.

MeSH terms

Allosteric Regulation
Animals
Antihypertensive Agents / chemical synthesis
Antihypertensive Agents / pharmacokinetics
Antihypertensive Agents / pharmacology*
HEK293 Cells
Humans
Hypertension / drug therapy*
Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
Male
Mice, Transgenic
Minor Histocompatibility Antigens
Molecular Docking Simulation
Piperazines / chemical synthesis
Piperazines / pharmacokinetics
Piperazines / pharmacology*
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / pharmacology*
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / metabolism
Rats, Sprague-Dawley
Structure-Activity Relationship
Thiazoles / chemical synthesis
Thiazoles / pharmacokinetics
Thiazoles / pharmacology*
WNK Lysine-Deficient Protein Kinase 1

Substances

(5-chloro-2-(2-((methyl)amino)thiazol-4-yl)pyridin-4-yl)(4-(4-chlorobenzyl)piperazin-1-yl)methanone
Antihypertensive Agents
Intracellular Signaling Peptides and Proteins
Minor Histocompatibility Antigens
Piperazines
Protein Kinase Inhibitors
Thiazoles
OXSR1 protein, human
WNK2 protein, human
Protein Serine-Threonine Kinases
WNK Lysine-Deficient Protein Kinase 1
WNK1 protein, human
WNK4 protein, human