"Hit" to lead optimization and chemoinformatic studies for a new series of Autotaxin inhibitors.
Eur J Med Chem
; 249: 115130, 2023 Mar 05.
Article
in En
| MEDLINE
| ID: mdl-36702053
ABSTRACT
Robust experimental evidence has highlighted the role of Autotaxin (ATX)/Lysophosphatidic acid (LPA) axis not only in the pathogenesis of chronic inflammatory conditions and especially in fibroproliferative diseases but also in several types of cancer. As a result, different series of substrate-, lipid-based and small-molecule ATX inhibitors have been identified thus far by both academia and pharma. The "crowning achievement" of these drug discovery campaigns was the development and entry of the first-in-class ATX inhibitor (ziritaxestat, GLPG-1690) in advanced clinical trials against idiopathic pulmonary fibrosis. Herein, the potency optimization efforts of a new series of Autotaxin inhibitors, namely 2-substituted-2,6-dihydro-4H-thieno[3,4-c]pyrazol-1-substituted amide, is described using a previously identified novel chemical scaffold as a "hit". The mode of inhibition of the most promising ATX inhibitors was investigated, while their cellular activity, aqueous solubility and cytotoxicity were evaluated. Our pharmacological results were corroborated by chemoinformatic tools (molecular docking and molecular dynamics simulations) deployed, to provide insight into the binding mechanism of the synthesized inhibitors to ATX.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Idiopathic Pulmonary Fibrosis
/
Neoplasms
Limits:
Humans
Language:
En
Journal:
Eur J Med Chem
Year:
2023
Document type:
Article
Affiliation country:
Grecia