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

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

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 reveali...

Full description

Saved in:
Bibliographic Details
Published in:Chemical biology & drug design Vol. 99; no. 3; pp. 496 - 503
Main Authors: Roy, Ashis, Sarkar, Tonmoy, Datta, Sebak, Maiti, Arup, Chakrabarti, Monali, Mondal, Trisha, Mondal, Chaitali, Banerjee, Apurba, Roy, Subhasis, Mukherjee, Soumen, Muley, Pragati, Chakraborty, Sabyasachi, Banerjee, Manish, Kundu, Mrinalkanti, Roy, Kuldeep K.
Format: Journal Article
Language:English
Published: England 01-03-2022
Subjects:
ADME
Administration, Oral
aminohydantoin
Animals
autotaxin
Binding Sites
docking
Drug Design
Drug Stability
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - metabolism
Enzyme Inhibitors - pharmacokinetics
Half-Life
Humans
Imidazoles - chemistry
in vitro
Indoles - chemistry
Indoles - metabolism
Indoles - pharmacokinetics
Microsomes, Liver - metabolism
Molecular Docking Simulation
Phosphoric Diester Hydrolases - chemistry
Phosphoric Diester Hydrolases - metabolism
Pyridines - chemistry
Rats
Rats, Sprague-Dawley
Stereoisomerism
docking
aminohydantoin
ADME
autotaxin
drug design
in vitro
PK
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 IC50 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 (CLint = 15.6 μl/min/mg; T1/2 = 113.2 min) with solubility of 4.82 μM and orally bioavailable, demonstrating its potential to be used for in vivo experiments. Intervention in the ATX‐LPA signaling cascade has been a promising strategy to treat various diseases and led to the discovery of novel molecular entities some of which progressed to different stages in clinical trials albeit varied success. We herein divulge structure‐based discovery of a polycyclic aminohydantoin derivative 1 as potent, non‐cytotoxic, metabolically stable, and orally bioavailable autotaxin inhibitor.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1747-0277
1747-0285
DOI:10.1111/cbdd.14017