Evidence map›Paper›PMID 29070696›Full record

ArticleMolecular pharmacology2017

Structural Determinants Influencing the Potency and Selectivity of Indazole-Paroxetine Hybrid G Protein-Coupled Receptor Kinase 2 Inhibitors.

Renee Bouley, Helen V Waldschmidt, M Claire Cato, Alessandro Cannavo, Jianliang Song, Joseph Y Cheung, Xin-Qiu Yao, Walter J Koch, Scott D Larsen, John J G Tesmer

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular pharmacology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.

0numbers the graph read from it
0cells of the map it votes in
15citing papers in PubMed
1.2field-weighted citation impact, top 21% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

15 citing papers in PubMed, 25 citations in OpenAlex.

  1. Article
  2. Logic-based machine learning predicts how escitalopram attenuates cardiomyocyte hypertrophy.Proceedings of the National Academy of Sciences of the United States of America · 2025
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  8. Targeting G protein-coupled receptor kinases (GRKs) to G protein-coupled receptors.Current opinion in endocrine and metabolic research · 2021
    Article
  9. Article
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  12. Review
  13. Article
  14. Review
  15. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

10 authors at 5 institutions in 1 country.

Renee BouleyLife Sciences Institute (R.B., H.V.W., M.C.C., J.J.G.T.), Departments of Medicinal Chemistry (H.V.W., S.D.L., J.J.G.T.), Pharmacology (R.B., J.J.G.T.), Biological Chemistry (M.C.C., J.J.G.T.), and Vahlteich Medicinal Chemistry Core, College of Pharmacy (H.V.W., S.D.L.), University of Michigan, Ann Arbor, Michigan; Department of Chemistry, Georgia State University, Atlanta, Georgia (X.-Q.Y.); Center for Translational Medicine, Temple University, Philadelphia, Pennsylvania (A.C., J.S., J.Y.C, W.J.K.); and Department of Biological Sciences, Purdue University, West Lafayette Indiana (J.J.G.T.).
Helen V WaldschmidtLife Sciences Institute (R.B., H.V.W., M.C.C., J.J.G.T.), Departments of Medicinal Chemistry (H.V.W., S.D.L., J.J.G.T.), Pharmacology (R.B., J.J.G.T.), Biological Chemistry (M.C.C., J.J.G.T.), and Vahlteich Medicinal Chemistry Core, College of Pharmacy (H.V.W., S.D.L.), University of Michigan, Ann Arbor, Michigan; Department of Chemistry, Georgia State University, Atlanta, Georgia (X.-Q.Y.); Center for Translational Medicine, Temple University, Philadelphia, Pennsylvania (A.C., J.S., J.Y.C, W.J.K.); and Department of Biological Sciences, Purdue University, West Lafayette Indiana (J.J.G.T.).
M Claire CatoLife Sciences Institute (R.B., H.V.W., M.C.C., J.J.G.T.), Departments of Medicinal Chemistry (H.V.W., S.D.L., J.J.G.T.), Pharmacology (R.B., J.J.G.T.), Biological Chemistry (M.C.C., J.J.G.T.), and Vahlteich Medicinal Chemistry Core, College of Pharmacy (H.V.W., S.D.L.), University of Michigan, Ann Arbor, Michigan; Department of Chemistry, Georgia State University, Atlanta, Georgia (X.-Q.Y.); Center for Translational Medicine, Temple University, Philadelphia, Pennsylvania (A.C., J.S., J.Y.C, W.J.K.); and Department of Biological Sciences, Purdue University, West Lafayette Indiana (J.J.G.T.).
Alessandro CannavoLife Sciences Institute (R.B., H.V.W., M.C.C., J.J.G.T.), Departments of Medicinal Chemistry (H.V.W., S.D.L., J.J.G.T.), Pharmacology (R.B., J.J.G.T.), Biological Chemistry (M.C.C., J.J.G.T.), and Vahlteich Medicinal Chemistry Core, College of Pharmacy (H.V.W., S.D.L.), University of Michigan, Ann Arbor, Michigan; Department of Chemistry, Georgia State University, Atlanta, Georgia (X.-Q.Y.); Center for Translational Medicine, Temple University, Philadelphia, Pennsylvania (A.C., J.S., J.Y.C, W.J.K.); and Department of Biological Sciences, Purdue University, West Lafayette Indiana (J.J.G.T.).
Jianliang SongLife Sciences Institute (R.B., H.V.W., M.C.C., J.J.G.T.), Departments of Medicinal Chemistry (H.V.W., S.D.L., J.J.G.T.), Pharmacology (R.B., J.J.G.T.), Biological Chemistry (M.C.C., J.J.G.T.), and Vahlteich Medicinal Chemistry Core, College of Pharmacy (H.V.W., S.D.L.), University of Michigan, Ann Arbor, Michigan; Department of Chemistry, Georgia State University, Atlanta, Georgia (X.-Q.Y.); Center for Translational Medicine, Temple University, Philadelphia, Pennsylvania (A.C., J.S., J.Y.C, W.J.K.); and Department of Biological Sciences, Purdue University, West Lafayette Indiana (J.J.G.T.).
Joseph Y CheungLife Sciences Institute (R.B., H.V.W., M.C.C., J.J.G.T.), Departments of Medicinal Chemistry (H.V.W., S.D.L., J.J.G.T.), Pharmacology (R.B., J.J.G.T.), Biological Chemistry (M.C.C., J.J.G.T.), and Vahlteich Medicinal Chemistry Core, College of Pharmacy (H.V.W., S.D.L.), University of Michigan, Ann Arbor, Michigan; Department of Chemistry, Georgia State University, Atlanta, Georgia (X.-Q.Y.); Center for Translational Medicine, Temple University, Philadelphia, Pennsylvania (A.C., J.S., J.Y.C, W.J.K.); and Department of Biological Sciences, Purdue University, West Lafayette Indiana (J.J.G.T.).
Xin-Qiu YaoLife Sciences Institute (R.B., H.V.W., M.C.C., J.J.G.T.), Departments of Medicinal Chemistry (H.V.W., S.D.L., J.J.G.T.), Pharmacology (R.B., J.J.G.T.), Biological Chemistry (M.C.C., J.J.G.T.), and Vahlteich Medicinal Chemistry Core, College of Pharmacy (H.V.W., S.D.L.), University of Michigan, Ann Arbor, Michigan; Department of Chemistry, Georgia State University, Atlanta, Georgia (X.-Q.Y.); Center for Translational Medicine, Temple University, Philadelphia, Pennsylvania (A.C., J.S., J.Y.C, W.J.K.); and Department of Biological Sciences, Purdue University, West Lafayette Indiana (J.J.G.T.).
Walter J KochLife Sciences Institute (R.B., H.V.W., M.C.C., J.J.G.T.), Departments of Medicinal Chemistry (H.V.W., S.D.L., J.J.G.T.), Pharmacology (R.B., J.J.G.T.), Biological Chemistry (M.C.C., J.J.G.T.), and Vahlteich Medicinal Chemistry Core, College of Pharmacy (H.V.W., S.D.L.), University of Michigan, Ann Arbor, Michigan; Department of Chemistry, Georgia State University, Atlanta, Georgia (X.-Q.Y.); Center for Translational Medicine, Temple University, Philadelphia, Pennsylvania (A.C., J.S., J.Y.C, W.J.K.); and Department of Biological Sciences, Purdue University, West Lafayette Indiana (J.J.G.T.).
Scott D LarsenLife Sciences Institute (R.B., H.V.W., M.C.C., J.J.G.T.), Departments of Medicinal Chemistry (H.V.W., S.D.L., J.J.G.T.), Pharmacology (R.B., J.J.G.T.), Biological Chemistry (M.C.C., J.J.G.T.), and Vahlteich Medicinal Chemistry Core, College of Pharmacy (H.V.W., S.D.L.), University of Michigan, Ann Arbor, Michigan; Department of Chemistry, Georgia State University, Atlanta, Georgia (X.-Q.Y.); Center for Translational Medicine, Temple University, Philadelphia, Pennsylvania (A.C., J.S., J.Y.C, W.J.K.); and Department of Biological Sciences, Purdue University, West Lafayette Indiana (J.J.G.T.).
John J G TesmerLife Sciences Institute (R.B., H.V.W., M.C.C., J.J.G.T.), Departments of Medicinal Chemistry (H.V.W., S.D.L., J.J.G.T.), Pharmacology (R.B., J.J.G.T.), Biological Chemistry (M.C.C., J.J.G.T.), and Vahlteich Medicinal Chemistry Core, College of Pharmacy (H.V.W., S.D.L.), University of Michigan, Ann Arbor, Michigan; Department of Chemistry, Georgia State University, Atlanta, Georgia (X.-Q.Y.); Center for Translational Medicine, Temple University, Philadelphia, Pennsylvania (A.C., J.S., J.Y.C, W.J.K.); and Department of Biological Sciences, Purdue University, West Lafayette Indiana (J.J.G.T.) jtesmer@purdue.edu.
Georgia State University · USJacobson Holman (United States) · USPurdue University West Lafayette · USTemple University · USUniversity of Michigan–Ann Arbor · US

Funding

Regulation of Beta-Adrenergic Receptor Signaling by S-NitrosylationP01HL075443 · NHLBI · DUKE UNIVERSITY · PI STAMLER, JONATHAN S. · 2004 to 2019
$26.1M
Targeted Cancer Therapeutics and Heart Failure: Mechanisms and Post-injury RepairP01HL091799 · NHLBI · THOMAS JEFFERSON UNIVERSITY · PI HOUSER, STEVEN R · 2008 to 2018
$23.1M
PKC alpha as a translational target in Heart FailureP01HL108806 · NHLBI · TEMPLE UNIV OF THE COMMONWEALTH · PI RABINOWITZ, JOSEPH E · 2012 to 2016
$11.3M
Structure, function, and inhibition of G protein-coupled receptor kinasesR01HL071818 · NHLBI · UNIVERSITY OF TEXAS AUSTIN · PI TESMER, JOHN · 2004 to 2023
$7.1M
MICHIGAN CHEMISTRY-BIOLOGY INTERFACE TRAINING PROGRAMT32GM008597 · NIGMS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI MONTGOMERY, JOHN · 1996 to 2018
$5.0M
Targeting GRK2 in the HeartR01HL061690 · NHLBI · THOMAS JEFFERSON UNIVERSITY · PI KOCH, WALTER J. · 1998 to 2022
$4.2M
Targeting GRK2 (BARK1) in Heart FailureR37HL061690 · NHLBI · THOMAS JEFFERSON UNIVERSITY · PI KOCH, WALTER J. · 2009 to 2018
$3.9M
Structure and Function of the LPLA2/LCAT Acyltransferase FamilyR01HL122416 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI TESMER, JOHN · 2015 to 2018
$1.9M
NHLBI NIH HHS P01 HL075443NHLBI NIH HHS P01 HL091799NHLBI NIH HHS P01 HL108806NHLBI NIH HHS R01 HL061690NHLBI NIH HHS R01 HL071818NHLBI NIH HHS R01 HL122416NHLBI NIH HHS R37 HL061690NIGMS NIH HHS T32 GM008597
6 · The paper itself

Abstract

G protein-coupled receptor kinases (GRKs) phosphorylate activated receptors to promote arrestin binding, decoupling from heterotrimeric G proteins, and internalization. GRK2 and GRK5 are overexpressed in the failing heart and thus have become therapeutic targets. Previously, we discovered two classes of GRK2-selective inhibitors, one stemming from GSK180736A, a Rho-associated coiled-coil containing kinase 1 (ROCK1) inhibitor, the other from paroxetine, a selective serotonin-reuptake inhibitor. These two classes of compounds bind to the GRK2 active site in a similar configuration but contain different hinge-binding "warheads": indazole and benzodioxole, respectively. We surmised from our prior studies that an indazole would be the stronger hinge binder and would impart increased potency when substituted for benzodioxole in paroxetine derivatives. To test this hypothesis, we synthesized a series of hybrid compounds that allowed us to compare the effects of inhibitors that differ only in the identity of the warhead. The indazole-paroxetine analogs were indeed more potent than their respective benzodioxole derivatives but lost selectivity. To investigate how these two warheads dictate selectivity, we determined the crystal structures of three of the indazole hybrid compounds (CCG224061, CCG257284, and CCG258748) in complex with GRK2-G

Indexed as

AnimalsG-Protein-Coupled Receptor Kinase 2G-Protein-Coupled Receptor Kinase 5HumansIndazolesMiceMice, Inbred C57BLModels, MolecularParoxetineProtein Kinase Inhibitorsrho-Associated KinasesSelective Serotonin Reuptake InhibitorsG-Protein-Coupled Receptor Kinase 2G-Protein-Coupled Receptor Kinase 5IndazolesParoxetineProtein Kinase Inhibitorsrho-Associated KinasesSelective Serotonin Reuptake Inhibitors

Identifiers

PMID29070696
PMCPMC5691592
OpenAlexW2766504508

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.