Abstract
In a previous report, we described the discovery of 1,4-azaindoles, a chemical series with excellent in vitro and in vivo antimycobacterial potency through noncovalent inhibition of decaprenylphosphoryl-β-d-ribose-2'-epimerase (DprE1). Nevertheless, high mouse metabolic turnover and phosphodiesterase 6 (PDE6) off-target activity limited its advancement. Herein, we report lead optimization of this series, culminating in potent, metabolically stable compounds that have a robust pharmacokinetic profile without any PDE6 liability. Furthermore, we demonstrate efficacy for 1,4-azaindoles in a rat chronic TB infection model. We believe that compounds from the 1,4-azaindole series are suitable for in vivo combination and safety studies.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alcohol Oxidoreductases
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Animals
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Antitubercular Agents / chemical synthesis*
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Antitubercular Agents / pharmacokinetics
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Antitubercular Agents / pharmacology
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Bacterial Proteins / antagonists & inhibitors
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Cyclic Nucleotide Phosphodiesterases, Type 6 / antagonists & inhibitors
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Disease Models, Animal
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Humans
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Indoles / chemical synthesis*
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Indoles / pharmacokinetics
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Mice
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Mycobacterium tuberculosis / drug effects
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Oxidoreductases / antagonists & inhibitors
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Rats
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Structure-Activity Relationship
Substances
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4-azaindole
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Antitubercular Agents
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Bacterial Proteins
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Indoles
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Oxidoreductases
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Alcohol Oxidoreductases
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DprE1 protein, Mycobacterium tuberculosis
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Cyclic Nucleotide Phosphodiesterases, Type 6