Τίτλος:
Synthesis of novel 2-pyrrolidinone and pyrrolidine derivatives and study of their inhibitory activity against autotaxin enzyme
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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. © 2019 Elsevier Ltd
Συγγραφείς:
Gerokonstantis, D.T.
Nikolaou, A.
Magkrioti, C.
Afantitis, A.
Aidinis, V.
Kokotos, G.
Moutevelis-Minakakis, P.
Περιοδικό:
BIOORGANIC AND MEDICINAL CHEMISTRY
Εκδότης:
Elsevier Ireland Ltd
Λέξεις-κλειδιά:
1 (4 fluorobenzyl) 5 oxo n [4 (4 sulfamoylbenzyloxy)benzyl] pyrrolidine 2 carboxamide; 1 (4 fluorobenzyl) 5 oxo n [4 [[4 (4,4,5,5 tetramethyl 1,3,2 dioxaborolan 2 yl)benzyl]oxy]benzyl]pyrrolidine 2 carboxamide; 1 benzyl 5 oxo n [4 (4 sulfamoylbenzyloxy)benzyl]pyrrolidine 2 carboxamide; 1 benzyl 5 oxo n [4 [[4 (4,4,5,5 tetramethyl 1,3,2 dioxaborolan 2 yl)benzyl] oxy]benzyl]pyrrolidine 2 carboxamide; 1 benzyl 5 oxo n [4 [[4 (4,4,5,5 tetramethyl 1,3,2 dioxaborolan 2 yl]benzyl]oxy] benzyl)pyrrolidine 2 carboxamide; 1 benzyl 5 oxo n [4 [[4 [[(tetrahydro 2h pyran 2 yl)oxy] carbamoyl] benzyl]oxy]benzyl]pyrrolidine 2 carboxamide; 1 benzyl n [4 (benzyloxy)benzyl] 5 oxopyrrolidine 2 carboxamide; 1 benzyl n [4 [(4 cyanobenzyl)oxy]benzyl] 5 oxopyrrolidine 2 carboxamide; 1 benzyl n [4 [(4 cyanobenzyl)oxy]benzyl]pyrrolidine 2 carboxamide; 2 pyrrolidinone; 5 oxo n [4 (4 sulfamoylbenzyloxy)benzyl] 1 [4 (trifluoromethyl)benzyl]pyrrolidine 2 carboxamide; autotaxin; boronic acid derivative; carboxylic acid; hydroxamic acid; methyl 4 [[4 [(1 benzyl 5 oxopyrrolidine 2 carboxamido) methyl] phenoxy]methyl] benzoic acid; methyl 4 [[4 [(1 benzyl 5 oxopyrrolidine 2 carboxamido) methyl]phenoxy]methyl] benzoic acid; methyl 4 [[4 [(1 benzylpyrrolidine 2 carboxamido)methyl] phenoxy]methyl]benzoic acid; methyl 4 [[4 [(5 oxopyrrolidine 2 carboxamido)methyl] phenoxy]methyl]benzoic acid; methyl 4 [[4 [[1 (4 bromobenzyl) 5 oxopyrrolidine 2 carboxamido] methyl] phenoxy]methyl]benzoic acid; methyl 4 [[4 [[1 (4 fluorobenzyl) 5 oxopyrrolidine 2 carboxamido] methyl]phenoxy] methyl] benzoic acid; methyl 4 [[4 [[1 (4 fluorobenzyl)pyrrolidine 2 carboxamido] methyl] phenoxy]methyl]benzoic acid; methyl 4 [[4 [[5 oxo 1 [4 (trifluoromethyl)benzyl]pyrrolidine 2 carboxamido]methyl]phenoxy]methyl]benzoic acid; n benzyl 1 [4 (benzyloxy)benzyl] 5 oxopyrrolidine 2 carboxamide; n [(1 benzyl 5 oxopyrrolidin 2 yl)methyl] 4 sulfamoylbenzamide; n [4 [(4 cyanobenzyl)oxy]benzyl] 1 (4 fluorobenzyl) 5 oxopyrrolidine 2 carboxamide; n,1 dibenzyl 5 oxopyrrolidine 2 carboxamide; pyrrolidine derivative; tert butyl 4 [2 [4 [[4 [(1 benzyl 5 oxopyrrolidine 2 carboxamido)methyl] phenoxy]methyl]benzamido]ethyl] 1h imidazole 1 carboxylic acid; unclassified drug; unindexed drug; alkylglycerophosphoethanolamine phosphodiesterase; enzyme inhibitor; phosphodiesterase; pyrrolidine; pyrrolidine derivative, Article; drug structure; drug synthesis; enzyme inhibition; IC50; in vitro study; inhibitory concentration; chemical structure; chemistry; dose response; human; metabolism; molecular model; structure activity relation; synthesis, Dose-Response Relationship, Drug; Enzyme Inhibitors; Humans; Models, Molecular; Molecular Structure; Phosphoric Diester Hydrolases; Pyrrolidines; Structure-Activity Relationship
DOI:
10.1016/j.bmc.2019.115216
