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Tytuł:
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Structure-based discovery of (S)-2-amino-6-(4-fluorobenzyl)-5,6,11,11a-tetrahydro-1H-imidazo[1',5':1,6]pyrido[3,4-b]indole-1,3(2H)-dione as low nanomolar, orally bioavailable autotaxin inhibitor.
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Autorzy:
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Roy A; TCG Lifesciences Pvt. Ltd., Kolkata, India.
Sarkar T; TCG Lifesciences Pvt. Ltd., Kolkata, India.
Datta S; TCG Lifesciences Pvt. Ltd., Kolkata, India.
Maiti A; TCG Lifesciences Pvt. Ltd., Kolkata, India.
Chakrabarti M; TCG Lifesciences Pvt. Ltd., Kolkata, India.
Mondal T; TCG Lifesciences Pvt. Ltd., Kolkata, India.
Mondal C; TCG Lifesciences Pvt. Ltd., Kolkata, India.
Banerjee A; TCG Lifesciences Pvt. Ltd., Kolkata, India.
Roy S; TCG Lifesciences Pvt. Ltd., Kolkata, India.
Mukherjee S; TCG Lifesciences Pvt. Ltd., Kolkata, India.
Muley P; TCG Lifesciences Pvt. Ltd., Kolkata, India.
Chakraborty S; TCG Lifesciences Pvt. Ltd., Kolkata, India.
Banerjee M; TCG Lifesciences Pvt. Ltd., Kolkata, India.
Kundu M; TCG Lifesciences Pvt. Ltd., Kolkata, India.
Roy KK; Department of Pharmaceutical Sciences, School of Health Sciences, UPES, Dehradun, India.
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Źródło:
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Chemical biology & drug design [Chem Biol Drug Des] 2022 Mar; Vol. 99 (3), pp. 496-503. Date of Electronic Publication: 2022 Jan 03.
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Typ publikacji:
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Journal Article
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Język:
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English
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Imprint Name(s):
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Original Publication: Oxford : Wiley-Blackwell, 2006-
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MeSH Terms:
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Drug Design*
Enzyme Inhibitors/*chemistry
Indoles/*chemistry
Phosphoric Diester Hydrolases/*chemistry
Administration, Oral ; Animals ; Binding Sites ; Drug Stability ; Enzyme Inhibitors/metabolism ; Enzyme Inhibitors/pharmacokinetics ; Half-Life ; Humans ; Imidazoles/chemistry ; Indoles/metabolism ; Indoles/pharmacokinetics ; Microsomes, Liver/metabolism ; Molecular Docking Simulation ; Phosphoric Diester Hydrolases/metabolism ; Pyridines/chemistry ; Rats ; Rats, Sprague-Dawley ; Stereoisomerism
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References:
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Contributed Indexing:
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Keywords: ADME; PK; aminohydantoin; autotaxin; docking; drug design; in vitro
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Substance Nomenclature:
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0 (Enzyme Inhibitors)
0 (Imidazoles)
0 (Indoles)
0 (Pyridines)
EC 3.1.4.- (Phosphoric Diester Hydrolases)
EC 3.1.4.39 (alkylglycerophosphoethanolamine phosphodiesterase)
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Entry Date(s):
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Date Created: 20211224 Date Completed: 20220307 Latest Revision: 20220307
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Update Code:
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20240104
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DOI:
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10.1111/cbdd.14017
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PMID:
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34951520
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Inhibition of extracellular secreted enzyme autotaxin (ATX) represents an attractive strategy for the development of new therapeutics to treat various diseases and a few inhibitors entered in clinical trials. We herein describe structure-based design, synthesis, and biological investigations revealing a potent and orally bioavailable ATX inhibitor 1. During the molecular docking and scoring studies within the ATX enzyme (PDB-ID: 4ZGA), the S-enantiomer (Gscore = -13.168 kcal/mol) of the bound ligand PAT-494 scored better than its R-enantiomer (Gscore = -9.562 kcal/mol) which corroborated with the reported observation and analysis of the results suggested the scope of manipulation of the hydantoin substructure in PAT-494. Accordingly, the docking-based screening of a focused library of 10 compounds resulted in compound 1 as a better candidate for pharmacological studies. Compound 1 was synthesized from L-tryptophan and evaluated against ATX enzymatic activities with an IC 50 of 7.6 and 24.6 nM in biochemical and functional assays, respectively. Further, ADME-PK studies divulged compound 1 as non-cytotoxic (19.02% cell growth inhibition at 20 μM in human embryonic kidney cells), metabolically stable against human liver microsomes (CL int = 15.6 μl/min/mg; T 1/2 = 113.2 min) with solubility of 4.82 μM and orally bioavailable, demonstrating its potential to be used for in vivo experiments.
(© 2021 John Wiley & Sons Ltd.)
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