Literature DB >> 31413810

Discovery of GSK2798745: A Clinical Candidate for Inhibition of Transient Receptor Potential Vanilloid 4 (TRPV4).

Carl A Brooks1, Linda S Barton1, David J Behm1, Hilary S Eidam1, Ryan M Fox1, Marlys Hammond1, Tram H Hoang1, Dennis A Holt1, Mark A Hilfiker1, Brian G Lawhorn1, Jaclyn R Patterson1, Patrick Stoy1, Theresa J Roethke1, Guosen Ye1, Steve Zhao1, Kevin S Thorneloe1, Krista B Goodman1, Mui Cheung1.   

Abstract

GSK2798745, a clinical candidate, was identified as an inhibitor of the transient receptor potential vanilloid 4 (TRPV4) ion channel for the treatment of pulmonary edema associated with congestive heart failure. We discuss the lead optimization of this novel spirocarbamate series and specifically focus on our strategies and solutions for achieving desirable potency, rat pharmacokinetics, and physicochemical properties. We highlight the use of conformational bias to deliver potency and optimization of volume of distribution and unbound clearance to enable desirable in vivo mean residence times.

Entities:  

Year:  2019        PMID： 31413810      PMCID： PMC6691566          DOI： 10.1021/acsmedchemlett.9b00274

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


  23 in total

1.  OTRPC4, a nonselective cation channel that confers sensitivity to extracellular osmolarity.

Authors:  R Strotmann; C Harteneck; K Nunnenmacher; G Schultz; T D Plant
Journal:  Nat Cell Biol       Date:  2000-10       Impact factor: 28.824

2.  Identification and characterization of a novel human vanilloid receptor-like protein, VRL-2.

Authors:  N S Delany; M Hurle; P Facer; T Alnadaf; C Plumpton; I Kinghorn; C G See; M Costigan; P Anand; C J Woolf; D Crowther; P Sanseau; S N Tate
Journal:  Physiol Genomics       Date:  2001-01-19       Impact factor: 3.107

Review 3.  The influence of drug-like concepts on decision-making in medicinal chemistry.

Authors:  Paul D Leeson; Brian Springthorpe
Journal:  Nat Rev Drug Discov       Date:  2007-11       Impact factor: 84.694

4.  Transient receptor potential vanilloid 4-mediated disruption of the alveolar septal barrier: a novel mechanism of acute lung injury.

Authors:  Diego F Alvarez; Judy A King; David Weber; Emile Addison; Wolfgang Liedtke; Mary I Townsley
Journal:  Circ Res       Date:  2006-09-28       Impact factor: 17.367

5.  Molecular determinants of permeation through the cation channel TRPV4.

Authors:  Thomas Voets; Jean Prenen; Joris Vriens; Hiroyuki Watanabe; Annelies Janssens; Ulrich Wissenbach; Matthias Bödding; Guy Droogmans; Bernd Nilius
Journal:  J Biol Chem       Date:  2002-07-01       Impact factor: 5.157

6.  High vascular pressure-induced lung injury requires P450 epoxygenase-dependent activation of TRPV4.

Authors:  Ming-Yuan Jian; Judy A King; Abu-Bakr Al-Mehdi; Wolfgang Liedtke; Mary I Townsley
Journal:  Am J Respir Cell Mol Biol       Date:  2007-10-25       Impact factor: 6.914

7.  N-((1S)-1-{[4-((2S)-2-{[(2,4-dichlorophenyl)sulfonyl]amino}-3-hydroxypropanoyl)-1-piperazinyl]carbonyl}-3-methylbutyl)-1-benzothiophene-2-carboxamide (GSK1016790A), a novel and potent transient receptor potential vanilloid 4 channel agonist induces urinary bladder contraction and hyperactivity: Part I.

Authors:  Kevin S Thorneloe; Anthony C Sulpizio; Zuojun Lin; David J Figueroa; Angela K Clouse; Gerald P McCafferty; Tim P Chendrimada; Erin S R Lashinger; Earl Gordon; Louise Evans; Blake A Misajet; Douglas J Demarini; Josephine H Nation; Linda N Casillas; Robert W Marquis; Bartholomew J Votta; Steven A Sheardown; Xiaoping Xu; David P Brooks; Nicholas J Laping; Timothy D Westfall
Journal:  J Pharmacol Exp Ther       Date:  2008-05-22       Impact factor: 4.030

8.  A comprehensive quantitative and qualitative evaluation of extrapolation of intravenous pharmacokinetic parameters from rat, dog, and monkey to humans. I. Clearance.

Authors:  Keith W Ward; Brian R Smith
Journal:  Drug Metab Dispos       Date:  2004-06       Impact factor: 3.922

9.  A comprehensive quantitative and qualitative evaluation of extrapolation of intravenous pharmacokinetic parameters from rat, dog, and monkey to humans. II. Volume of distribution and mean residence time.

Authors:  Keith W Ward; Brian R Smith
Journal:  Drug Metab Dispos       Date:  2004-06       Impact factor: 3.922

10.  Heat-evoked activation of the ion channel, TRPV4.

Authors:  Ali Deniz Güler; Hyosang Lee; Tohko Iida; Isao Shimizu; Makoto Tominaga; Michael Caterina
Journal:  J Neurosci       Date:  2002-08-01       Impact factor: 6.167
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  6 in total

1.  COVID-19: Urgent Reconsideration of Lung Edema as a Preventable Outcome: Inhibition of TRPV4 As a Promising and Feasible Approach.

Authors:  Wolfgang Kuebler; Sven-Eric Jordt; Wolfgang Liedtke
Journal:  SSRN       Date:  2020-03-23

2.  Identification, Synthesis, and Characterization of a Major Circulating Human Metabolite of TRPV4 Antagonist GSK2798745.

Authors:  Joseph E Pero; John J McAtee; David J Behm; Jacques Briand; Grazyna Graczyk-Millbrandt; Karl Erhard; Andrew D Roberts; Ralph A Rivero; Dennis A Holt; Brian G Lawhorn
Journal:  ACS Med Chem Lett       Date:  2021-08-30       Impact factor: 4.632

Review 3.  Calcium-Permeable Channels and Endothelial Dysfunction in Acute Lung Injury.

Authors:  Ying Hao; Zhuang Wang; Francis Frimpong; Xingjuan Chen
Journal:  Curr Issues Mol Biol       Date:  2022-05-16       Impact factor: 2.976

Review 4.  Role of the purinergic signaling network in lung ischemia-reperfusion injury.

Authors:  Nathan Haywood; Huy Q Ta; Evan Rotar; Zdravka Daneva; Swapnil K Sonkusare; Victor E Laubach
Journal:  Curr Opin Organ Transplant       Date:  2021-04-01       Impact factor: 2.269

5.  Urgent reconsideration of lung edema as a preventable outcome in COVID-19: inhibition of TRPV4 represents a promising and feasible approach.

Authors:  Wolfgang M Kuebler; Sven-Eric Jordt; Wolfgang B Liedtke
Journal:  Am J Physiol Lung Cell Mol Physiol       Date:  2020-05-13       Impact factor: 5.464

6.  With-No-Lysine Kinase 1 (WNK1) Augments TRPV4 Function in the Aldosterone-Sensitive Distal Nephron.

Authors:  Viktor N Tomilin; Kyrylo Pyrshev; Naghmeh Hassanzadeh Khayyat; Oleg Zaika; Oleh Pochynyuk
Journal:  Cells       Date:  2021-06-12       Impact factor: 6.600
  6 in total

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