Abstract
The transient receptor potential cation channel 5 (TRPC5) has been previously shown to affect podocyte survival in the kidney. As such, inhibitors of TRPC5 are interesting candidates for the treatment of chronic kidney disease (CKD). Herein, we report the synthesis and biological characterization of a series of N-heterocyclic-1-benzyl-1H-benzo[d]imidazole-2-amines as selective TRPC5 inhibitors. Work reported here evaluates the benzimidazole scaffold and substituents resulting in the discovery of AC1903, a TRPC5 inhibitor that is active in multiple animal models of CKD.
Keywords:
AC1903; Chronic kidney disease; Inhibitor; TRPC5; Transient receptor potential cation channel 5.
Copyright © 2018 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Amines / chemical synthesis
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Amines / chemistry
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Amines / pharmacology*
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Animals
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Drug Design
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Heterocyclic Compounds / chemical synthesis
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Heterocyclic Compounds / chemistry
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Heterocyclic Compounds / pharmacology*
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Humans
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Imidazoles / chemical synthesis
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Imidazoles / chemistry
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Imidazoles / pharmacology*
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Indazoles / chemical synthesis
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Indazoles / chemistry
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Indazoles / pharmacology*
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Molecular Structure
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Renal Insufficiency, Chronic / drug therapy*
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Renal Insufficiency, Chronic / metabolism
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Structure-Activity Relationship
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TRPC Cation Channels / antagonists & inhibitors*
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TRPC Cation Channels / chemical synthesis
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TRPC Cation Channels / chemistry
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TRPC Cation Channels / metabolism
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TRPC Cation Channels / pharmacology
Substances
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AC1903
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Amines
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Heterocyclic Compounds
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Imidazoles
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Indazoles
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TRPC Cation Channels
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TRPC5 protein, human