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Bioorg Med Chem. 2020 Jan 15;28(2):115216. doi: 10.1016/j.bmc.2019.115216. Epub 2019 Dec 9.

Synthesis of novel 2-pyrrolidinone and pyrrolidine derivatives and study of their inhibitory activity against autotaxin enzyme.

Author information

1
Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 15771, Greece.
2
Division of Immunology, Biomedical Sciences Research Center "Alexander Fleming", Athens 16672, Greece.
3
NovaMechanics Ltd, Nicosia 1065, Cyprus.
4
Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 15771, Greece. Electronic address: pminakak@chem.uoa.gr.

Abstract

Autotaxin (ATX), a glycoprotein (~125 kDa) isolated as an autocrine motility factor from melanoma cells, belongs to a seven-membered family of ectonucleotide pyrophosphatase/phosphodiesterase (ENPP), and exhibits lysophospholipase D activity. ATX is responsible for the hydrolysis of lysophosphatidylcholine (LPC) to produce the bioactive lipid lysophosphatidic acid (LPA), which is upregulated in a variety of pathological inflammatory conditions, including fibrosis, cancer, liver toxicity and thrombosis. Given its role in human disease, the ATX-LPA axis is an interesting target for therapy, and the development of novel potent ATX inhibitors is of great importance. In the present work a novel class of ATX inhibitors, optically active derivatives of 2-pyrrolidinone and pyrrolidine heterocycles were synthesized. Some of them exhibited interesting in vitro activity, namely the hydroxamic acid 16 (IC50 700 nM) and the carboxylic acid 40b (IC50 800 nM), while the boronic acid derivatives 3k (IC50 50 nM), 3l (IC50 120 nM), 3 m (IC50 180 nM) and 21 (IC50 35 nM) were found to be potent inhibitors of ATX.

KEYWORDS:

2-pyrrolidinones; Autotaxin; Inhibitor; Pyrrolidines

PMID:
31864778
DOI:
10.1016/j.bmc.2019.115216

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