Evidence map›Paper›PMID 32327351›Full record

ArticleBioorganic & medicinal chemistry2020

Synthesis and structure-activity relationships of thieno[2,3-d]pyrimidines as atypical protein kinase C inhibitors to control retinal vascular permeability and cytokine-induced edema.

Xuwen Liu, Michael W Wilson, Kun Liu, Pil Lee, Larisa Yeomans, Susan E Hagen, Cheng-Mao Lin, Bo Wen, Duxin Sun, Andrew D White and 2 more

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

Article in Bioorganic & medicinal chemistry, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
0.2field-weighted citation impact, top 54% 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

0 citing papers in PubMed, 2 citations in OpenAlex.

No citing paper in PubMed yet.

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

12 authors at 1 institution in 1 country.

Xuwen LiuDepartment of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI 48105, USA.
Michael W WilsonDepartment of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, USA; Vahlteich Medicinal Chemistry Core, University of Michigan, Ann Arbor, MI 48109, USA.
Kun LiuDepartment of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, USA; Vahlteich Medicinal Chemistry Core, University of Michigan, Ann Arbor, MI 48109, USA.
Pil LeeDepartment of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, USA; Vahlteich Medicinal Chemistry Core, University of Michigan, Ann Arbor, MI 48109, USA.
Larisa YeomansDepartment of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, USA.
Susan E HagenDepartment of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, USA; Vahlteich Medicinal Chemistry Core, University of Michigan, Ann Arbor, MI 48109, USA.
Cheng-Mao LinDepartment of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI 48105, USA.
Bo WenDepartment of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA.
Duxin SunDepartment of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA.
Andrew D WhiteDepartment of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, USA; Vahlteich Medicinal Chemistry Core, University of Michigan, Ann Arbor, MI 48109, USA.
Hollis D ShowalterDepartment of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, USA.
David A AntonettiDepartment of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI 48105, USA; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: dantonet@med.umich.edu.
University of Michigan–Ann Arbor · US

Funding

SPECIAL ASSAY COREP30DK036836 · NIDDK · JOSLIN DIABETES CENTER · PI ROHIT N. KULKARNI · 1986 to 2026
$50.5M
Regional Pilot And Feasibility Study Grants ProgramP30DK020572 · NIDDK · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Mehboob A Hussain · 2013 to 2026
$24.3M
VIVARIUM MODULEP30EY007003 · NEI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI David Antonetti · 1987 to 2026
$17.6M
Unraveling the role of tPA in the neurovascular unitR01HL055374 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI David Antonetti, Daniel A Lawrence · 1995 to 2026
$8.6M
MECHANISMS OF RETINAL VASCULAR PERMEABILITY IN DIABETESR01EY012021 · NEI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI ANTONETTI, DAVID · 1998 to 2024
$8.6M
Discovering novel atypical PKC inhibitors as in vivo chemical probes - Supplement to Promote DiversityR01EY023725 · NEI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI ANTONETTI, DAVID · 2014 to 2016
$1.6M
NEI NIH HHS P30 EY007003NEI NIH HHS R01 EY012021NEI NIH HHS R01 EY023725NHLBI NIH HHS R01 HL055374NIDDK NIH HHS P30 DK020572NIDDK NIH HHS P30 DK036836
6 · The paper itself

Abstract

Studies demonstrate that small molecule targeting of atypical protein kinase C (aPKC) may provide an effective means to control vascular permeability, prevent edema, and reduce inflammation providing novel and important alternatives to anti-VEGF therapies for certain blinding eye diseases. Based on a literature tricyclic thieno[2,3-d]pyrimidine lead (1), an ATP-competitive inhibitor of the aPKC iota (ι) and aPKC zeta (ζ) isoforms, we have synthesized a small series of compounds in 1-2 steps from a readily available chloro intermediate. A single pyridine congener was also made using 2D NMR to assign regiochemistry. Within the parent pyrimidine series, a range of potencies was observed against aPKCζ whereas the pyridine congener was inactive. Selected compounds were also tested for their effect toward VEGF-induced permeability in BREC cells. The most potent of these (7l) was further assayed against the aPKCι isoform and showed a favorable selectivity profile against a panel of 31 kinases, including kinases from the AGC superfamily, with a focus on PKC isoforms and kinases previously shown to affect permeability. Further testing of 7l in a luciferase assay in HEK293 cells showed an ability to prevent TNF-α induced NFκB activation while not having any effect on cell survival. Intravitreal administration of 7l to the eye yielded a complete reduction in permeability in a test to determine whether the compound could block VEGF- and TNFα-induced permeability across the retinal vasculature in a rat model. The compound in mice displayed good microsomal stability and in plasma moderate exposure (AUC and C

Indexed as

AnimalsCytokinesDose-Response Relationship, DrugEdemaFemaleHEK293 CellsHumansMiceMolecular StructureProtein Kinase CProtein Kinase InhibitorsPyrimidinesRatsRats, Long-EvansStructure-Activity RelationshipVascular Endothelial Growth Factor ACytokinesPKC-3 proteinProtein Kinase CProtein Kinase InhibitorsPyrimidinesthieno(2,3-d)pyrimidineVascular Endothelial Growth Factor AVEGFA protein, humanatypical protein kinase C (aPKC)Blinding eye diseasesHomology modelSARThieno[2,3-d]pyrimidine inhibitorsTumor necrosis factor-α (TNFα)Vascular endothelial growth factor (VEGF)Vascular permeability

Identifiers

PMID32327351
PMCPMC7318885
OpenAlexW3014705835

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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.