Findlay, AD; Foot, JS; Buson, A; Deodhar, M; Jarnicki, AG; Hansbro, PM; Liu, G; Schilter, H; Turner, CI; Zhou, W; Jarolimek, W
Lysyl oxidase-like 2 (LOXL2) is a secreted enzyme that catalyzes the formation of cross-links in extracellular matrix proteins, namely, collagen and elastin, and is indicated in fibrotic diseases. Herein, we report the identification and subsequent optimization of a series of indole-based fluoroallylamine inhibitors of LOXL2. The result of this medicinal chemistry campaign is PXS-5120A (12k), a potent, irreversible inhibitor that is >300-fold selective for LOXL2 over LOX. PXS-5120A also shows potent inhibition of LOXL3, an emerging therapeutic target for lung fibrosis. Key to the development of this compound was the utilization of a compound oxidation assay. PXS-5120A was optimized to show negligible substrate activity in vitro for related amine oxidase family members, leading to metabolic stability. PXS-5120A, in a pro-drug form (PXS-5129A, 12o), displayed anti-fibrotic activity in models of liver and lung fibrosis, thus confirming LOXL2 as an important target in diseases where collagen cross-linking is implicated. Copyright © 2019 American Chemical Society.
(s,z) 4 (4 amino 2 fluorobut 2 enyloxy) n (1 phenyl ethyl) benzenesulfonamide; (z) 1 (4 ((tert butoxycarbonyl)amino) 2 fluorobut 2 en 1 yl) 3 (3 (n,n dimethylsulfamoyl) phenyl) 2 methyl 1h indole 5 carboxylic acid; (z) 1 (4 amino 2 fluorobut 2 en 1 yl) 3 (3 (n,n dimethylsulfamoyl)phenyl) n,n,2 trimethyl 1h indole 5 carboxamide hydrochloride; (z) 3 (1 (4 amino 2 fluorobut 2 en 1 yl) 1h pyrrol 3 yl) n,n dimethylbenzenesulfonamide hydrochloride; (z) 3 (1 (4 amino 2 fluorobut 2 en 1 yl) 2 methyl 1h indol 3 yl) n,n dimethylbenzenesulfonamide hydrochloride; (z) 3 fluoro 4 (4 ((2 (methylsulfonyl)phenoxy)methyl) 1h 1,2,3 triazol 1 yl)but 2 en 1 amine hydrochloride; (z) 3 fluoro 4 (4 ((3 (methylsulfonyl)phenoxy)methyl) 1h 1,2,3 triazol 1 yl)but 2 en 1 amine hydrochloride; (z) 3 fluoro 4 (4 ((4 (methylsulfonyl)phenoxy)methyl) 1h 1,2,3 triazol 1 yl)but 2 en 1 amine hydrochloride; (z) 3 fluoro 4 (4 (phenoxymethyl) 1h 1,2,3 triazol 1 yl)but 2 en 1 amine Hydrochloride; (z) 4 ((1 (4 amino 2 fluorobut 2 en 1 yl) 1h 1,2,3 triazol 4 yl) methyl) n,n dimethylbenzenesulfonamide hydrochloride; (z) 4 ((1 (4 amino 2 fluorobut 2 enyl) 1h 1,2,3 triazol 4 yl) methoxy) 3 chloro n,n dimethylbenzenesulfonamide hydrochloride; (z) 4 ((1 (4 amino 2 fluorobut 2 enyl) 1h 1,2,3 triazol 4 yl) methoxy) n,n dimethylbenzamide hydrochloride; (z) 4 ((1 (4 amino 2 fluorobut 2 enyl) 1h 1,2,3 triazol 4 yl) methoxy) n,n dimethylbenzenesulfonamide hydrochloride; (z) 4 ((1 (4 amino 2 fluorobut 2 enyl) 1h 1,2,3 triazol 4 yl) methylamino) n,n dimethylbenzene sulfonamide hydrochloride; (z) 4 (1 (4 amino 2 fluorobut 2 en 1 yl) 1h 1,2,3 triazol 4 yl) n,n dimethylbenzenesulfonamide hydrochloride; (z) 4 (1 (4 amino 2 fluorobut 2 en 1 yl) 1h pyrrol 3 yl) n,n dimethylbenzenesulfonamide hydrochloride; (z) 4 (1 (4 amino 2 fluorobut 2 en 1 yl) 2 methyl 1h indol 3 yl) n,n dimethylbenzenesulfonamide hydrochloride; (z) 4 (4 ((4 tert butylphenoxy)methyl) 1h 1,2,3 triazol 1 yl) 3 fluorobut 2 en 1 amine hydrochloride; (z) ethyl 1 (4 ((tert butoxycarbonyl)amino) 2 fluorobut 2 en 1 yl) 3 (3 (n,n dimethylsulfamoyl)phenyl) 2 methyl 1h indole 5 carboxylate; (z) tert butyl 3 fluoro 4 hydroxybut 2 enylcarbamate; (z) tert butyl 4 azido 3 fluorobut 2 enylcarbamate; (z) tert butyl 4 bromo 3 fluorobut 2 enylcarbamate; (z) tert butyl(4 (5 (dimethylcarbamoyl) 3 (3 (n,n dimethylsulfamoyl)phenyl) 2 methyl 1h indol 1 yl) 3 fluorobut 2 en 1 yl) carbamate; enzyme inhibitor; fluoroallylamine inhibitor; Lysyl oxidase like 2; n,n dimethyl 4 prop 2 ynoxy benzenesulfonamide; protein lysine 6 oxidase; pxs 5129a; unclassified drug; unindexed drug; amine; enzyme inhibitor; protein lysine 6 oxidase; triazole derivative; animal experiment; animal model; animal tissue; antifibrotic activity; Article; column chromatography; controlled study; dilution; drug identification; drug purity; drug synthesis; enzymatic assay; female; fluorine nuclear magnetic resonance; high performance liquid chromatography; human; human cell; liquid chromatography-mass spectrometry; liver cirrhosis; liver fibrosis; lung fibrosis; male; medicinal chemistry; metabolic stability; mouse; nonhuman; oxidation; proton nuclear magnetic resonance; thin layer chromatography; animal; chemistry; drug design; Amines; Animals; Drug Design; Enzyme Inhibitors; Humans; Mice; Protein-Lysine 6-Oxidase; Triazoles