Τίτλος:
Hydroxamic Acids Constitute a Novel Class of Autotaxin Inhibitors that Exhibit in Vivo Efficacy in a Pulmonary Fibrosis Model
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Autotaxin (ATX) catalyzes the hydrolysis of lysophosphatidylcholine (LPC) generating the lipid mediator lysophosphatidic acid (LPA). Both ATX and LPA are involved in various pathological inflammatory conditions, including fibrosis and cancer, and have attracted great interest as medicinal targets over the past decade. Thus, the development of novel potent ATX inhibitors is of great importance. We have developed a novel class of ATX inhibitors containing the zinc binding functionality of hydroxamic acid. Such novel hydroxamic acids that incorporate a non-natural δ-amino acid residue exhibit high in vitro inhibitory potency over ATX (IC 50 values 50-60 nM). Inhibitor 32, based on δ-norleucine, was tested for its efficacy in a mouse model of pulmonary inflammation and fibrosis induced by bleomycin and exhibited promising efficacy. The novel hydroxamic ATX inhibitors provide excellent tools for the study of the role of the enzyme and could contribute to the development of novel therapeutic agents for the treatment of fibrosis and other chronic inflammatory diseases. © 2018 American Chemical Society.
Συγγραφείς:
Nikolaou, A.
Ninou, I.
Kokotou, M.G.
Kaffe, E.
Afantitis, A.
Aidinis, V.
Kokotos, G.
Περιοδικό:
Journal of Medicinal Chemistry
Εκδότης:
American Chemical Society
Λέξεις-κλειδιά:
2 [4 [6 oxo 6 (phenylamino)hexanamido]phenyl]acetic acid; 4 fluoro n [5 [[4 [2 (hydroxyamino) 2 oxoethyl]phenyl]amino] 5 oxopentyl]benzamide; 5 (4 butoxyphenyl) n [4 [2 (hydroxyamino) 2 oxoethyl]phenyl]pentanamide; 5 [(1,1' biphenyl) 4 yl] n [4 [2 (hydroxyamino) 2 oxoethyl]phenyl]pentanamide; autotaxin; bleomycin; enzyme inhibitor; hydroxamic acid derivative; methyl 6 (hydroxyamino) 6 oxo 2 (7 phenylheptanamido)hexanoate; methyl 6 (hydroxyamino) 6 oxo 2 [6 oxo 6 (phenylamino)hexanamido]hexanoate; methyl n2 (5 benzamidopentanoyl) n5 hydroxyglutaminate; methyl n2 [6 [(4 ethoxyphenyl)amino] 6 oxohexanoyl] n5 hydroxyglutaminate; methyl n2 [6 [(4 fluorophenyl)amino] 6 oxohexanoyl] n5 hydroxyglutaminate; methyl n5 hydroxy n2 [6 oxo 6 (phenylamino)hexanoyl]glutaminate; methyl n5 hydroxy n2 [6 [(4 methoxyphenyl)amino] 6 oxohexanoyl]glutaminate; n hydroxy 2 [4 [2 (4 octylphenoxy)acetamido]phenyl]acetamide; n [4 [2 (hydroxyamino) 2 oxoethyl]phenyl] 3 (4 octylphenyl)propanamide; n [4 [2 (hydroxyamino) 2 oxoethyl]phenyl] 4 octylbenzamide; n [4 [2 (hydroxyamino) 2 oxoethyl]phenyl] 7 phenylheptanamide; n [4 [2 (hydroxyamino) 2 oxoethyl]phenyl]decanamide; n [4 [2 (hydroxyamino) 2 oxoethyl]phenyl]tetradecanamide; n [5 [[4 [2 (hydroxyamino) 2 oxoethyl]phenyl]amino] 5 oxopentyl] 4 methoxybenzamide; n [5 [[4 [2 (hydroxyamino) 2 oxoethyl]phenyl]amino] 5 oxopentyl]benzamide; n1 [1 (hydroxyamino) 1 oxononan 5 yl] n6 phenyladipamide; n1 [1,5 bis(hydroxyamino) 1,5 dioxopentan 2 yl] n6 phenyladipamide; n1 [4 (3,3,4,4,4 pentafluoro 2 oxobutyl)phenyl] n6 phenyladipamide; n1 [4 [2 (hydroxyamino) 2 oxoethyl]phenyl] n6 phenyladipamide; n1 [4 [2 (hydroxyamino) 2 oxoethyl]phenyl] n8 phenyloctanediamide; unclassified drug; unindexed drug; [4 [6 oxo 6 (phenylamino)hexanamido]phenyl]boronic acid; alkylglycerophosphoethanolamine phosphodiesterase; bleomycin; hydroxamic acid; phosphodiesterase; phosphodiesterase inhibitor, animal experiment; animal model; Article; controlled study; drug design; drug efficacy; drug potency; drug screening; drug synthesis; female; IC50; in vitro study; in vivo study; lung fibrosis; male; mouse; nonhuman; pneumonia; animal; blood; chemical structure; chemically induced; chemistry; enzyme active site; lung fibrosis; metabolism; molecular docking; structure activity relation; synthesis, Animals; Bleomycin; Catalytic Domain; Drug Design; Hydroxamic Acids; Mice; Molecular Docking Simulation; Molecular Structure; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Pulmonary Fibrosis; Structure-Activity Relationship
DOI:
10.1021/acs.jmedchem.8b00232
