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

Journal Article · · Journal of Medicinal Chemistry
ORCiD logo [1];  [2];  [3];  [3];  [3];  [4];  [3];  [3];  [5];  [6];  [3];  [7];  [8];  [5];  [3];  [9];  [3];  [1]; ORCiD logo [3];  [3] more »;  [3];  [10];  [11];  [12];  [1] « less
  1. Novartis Inst. for BioMedical Research, Inc., Cambridge, MA (United States); Novartis Inst. for BioMedical Research, Ibaraki (Japan)
  2. Novartis Inst. for BioMedical Research, Inc., Cambridge, MA (United States); Constellation Pharmaceuticals, Cambridge, MA (United States)
  3. Novartis Inst. for BioMedical Research, Inc., Cambridge, MA (United States)
  4. Novartis Pharmaceuticals Corporation, East Hanover, NJ (United States); Rigel BioPharma Consulting LLC, Berkeley Heights, NJ (United States)
  5. Novartis Inst. for BioMedical Research, Inc., Cambridge, MA (United States); Novartis Inst. for BioMedical Research, Inc., Ibaraki (Japan)
  6. Novartis Pharmaceuticals Corporation, East Hanover, NJ (United States); Insmed, Inc., Lake Hiawatha, NJ (United States)
  7. Novartis Pharmaceuticals Corporation, East Hanover, NJ (United States)
  8. Novartis Inst. for BioMedical Research, Inc., Cambridge, MA (United States); Transamerica, Leominster, MA (United States)
  9. Novartis Inst. for BioMedical Research, Inc., Cambridge, MA (United States); Takeda Pharmaceuticals U.S.A., Inc., Cambridge, MA (United States)
  10. Novartis Inst. for BioMedical Research, Ibaraki (Japan); FujiFilm Corporation, Kanagawa (Japan)
  11. Novartis Inst. for BioMedical Research, Inc., Cambridge, MA (United States); Janssen Pharmaceutical K.K., Tokyo (Japan)
  12. Novartis Inst. for BioMedical Research, Inc., Cambridge, MA (United States); Short Path Distillery, Inc., Arlington, MA (United States)
+ Show Author Affiliations

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. Furthermore, 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.

Research Organization:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE
OSTI ID:
1404996
Journal Information:
Journal of Medicinal Chemistry, Vol. 60, Issue 16; ISSN 0022-2623
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 25 works
Citation information provided by
Web of Science

References (17)

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Strategies for the Selective Regulation of Kinases with Allosteric Modulators: Exploiting Exclusive Structural Features journal December 2012
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Expanding the Opportunities for Modulating Kinase Targets with Allosteric Approaches journal November 2016
Rapid assessment of a novel series of selective CB2 agonists using parallel synthesis protocols: A Lipophilic Efficiency (LipE) analysis journal August 2009
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Metabolic Soft Spot Identification and Compound Optimization in Early Discovery Phases Using MetaSite and LC-MS/MS Validation journal January 2009
Predicting Regioselectivity and Lability of Cytochrome P450 Metabolism Using Quantum Mechanical Simulations journal October 2016
Altering Metabolic Profiles of Drugs by Precision Deuteration: Reducing Mechanism-Based Inhibition of CYP2D6 by Paroxetine journal May 2015
PKPD modelling of the interrelationship between mean arterial BP, cardiac output and total peripheral resistance in conscious rats: Drug effects on the CVS journal July 2013

Cited By (4)

Sympathetic regulation of NCC in norepinephrine-evoked salt-sensitive hypertension in Sprague-Dawley rats journal December 2019
Characterization of chemical components with diuretic potential from Pyrrosia petiolosa journal June 2020
Characterization of chemical components with diuretic potential from Pyrrosia petiolosa text January 2020
Characterization of chemical components with diuretic potential from Pyrrosia petiolosa text January 2020

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Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
60 APPLIED LIFE SCIENCES
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anatomy
inhibition
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