Synthesis of novel 2-pyrrolidinone and pyrrolidine derivatives and study of their inhibitory activity against autotaxin enzyme.
Gerokonstantis DT, Nikolaou A, Magkrioti C, Afantitis A, Aidinis V, Kokotos G, Moutevelis-Minakakis P.
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 (IC<sub>50</sub> 700 nM) and the carboxylic acid 40b (IC<sub>50</sub> 800 nM), while the boronic acid derivatives 3k (IC<sub>50</sub> 50 nM), 3l (IC<sub>50</sub> 120 nM), 3 m (IC<sub>50</sub> 180 nM) and 21 (IC<sub>50</sub> 35 nM) were found to be potent inhibitors of ATX.