US EPA

7460324 

Journal Article 

Synthesis and structure activity relationships of glycine amide derivatives as novel Vascular Adhesion Protein-1 inhibitors 

Yamaki, S; Suzuki, D; Fujiyasu, J; Neya, M; Nagashima, A; Kondo, M; Akabane, T; Kadono, K; Moritomo, A; Yoshihara, K 

2017 

Yes 

Bioorganic & Medicinal Chemistry
ISSN: 0968-0896
EISSN: 1464-3391 

Elsevier Ltd 

25 

1 

187-201 

English 

10.1016/j.bmc.2016.10.025 

Vascular Adhesion Protein-1 (VAP-1) is a promising therapeutic target for the treatment of several inflammatory-related diseases including diabetic microvascular complication. We identified glycine amide derivative 3 as a novel structure with moderate VAP-1 inhibitory activity. Structure-activity relationship studies of glycine amide derivatives revealed that the tertiary amide moiety is important for stability in rat blood and that the position of substituents on the left phenyl ring plays an important role in VAP-1 inhibitory activity. We also found that low TPSA values and weak basicity are both important for high PAMPA values for glycine amide derivatives. These findings led to the identification of a series of orally active compounds with enhanced VAP-1 inhibitory activity. Of these compounds, 4g exhibited the most potent ex vivo efficacy, with plasma VAP-1 inhibitory activity of 60% after oral administration at 1 mg/kg. © 2016 Elsevier Ltd 

Diabetic microvascular complication; Glycine amide; PAMPA; Vascular Adhesion Protein-1; 3' [[glycyl(methyl)amino]methyl]biphenyl 4 carboxamide; 3' [[glycyl(methyl)amino]methyl]biphenyl 4 carboxylic acid; 3' [[[n (tert butoxycarbonyl)glycyl](methyl)amino]methyl]biphenyl 4 carboxylic acid; amide; methyl 3' [[[n (tert butoxycarbonyl)glycyl](methyl)amino]methyl]biphenyl 4 carboxylate; n ethyl 3' [[glycyl(methyl)amino]methyl]biphenyl 4 carboxamide; n isopropyl n [[4' (morpholin 4 yl)biphenyl 3 yl]methyl]glycinamide tartrate; n methyl 1 [4' (morpholin 4 yl)biphenyl 3 yl]methanamine; n methyl n [[4' (morpholin 4 yl)biphenyl 3 yl]methyl]beta alaninamide tartrate; n methyl n [[4' (morpholin 4 yl)biphenyl 3 yl]methyl]glycinamide ethanedioate; n methyl n [[4' (morpholin 4 ylcarbonyl)biphenyl 3 yl]methyl]glycinamide tartrate; n methyl n [[40 (4 methylpiperazin 1 yl)biphenyl 3 yl]methyl]glycinamide tartrate; n [(2' chlorobiphenyl 3 yl)methyl]n methylglycinamide; n [(3' hlorobiphenyl 3 yl)methyl]n methylglycinamide ethanedioate; n [(4' acetamidobiphenyl 3 yl)methyl]n methylglycinamide; n [(4' chlorobiphenyl 3 yl)methyl]n methylglycinamide; n [3' [[glycyl(methyl)amino]methyl]biphenyl 4 yl]morpholine 4 carboxamide ethanedioate; n [[4 '[(diethylamino)methyl]biphenyl 3 yl]methyl]n methylglycinamide; n [[4' [(dimethylcarbamoyl)amino]biphenyl 3 yl]methyl]n methylglycinamide ethanedioate; n [[40 (dimethylamino)biphenyl 3 yl]methyl]n methylglycinamide ethanedioate; n(biphenyl 3 ylmethyl)glycinamide; n(biphenyl 3 ylmethyl)n methylglycinamide; n,2 dimethyl n [[4' (morpholin 4 yl)biphenyl 3 yl]methyl]alaninamide tartrate; n,n diethyl 3' [[glycyl(methyl)amino]methyl]biphenyl 4 carboxamide ethanedioate; protein inhibitor; tert butyl [2 [(3 bromobenzyl)(methyl)amino] 2 oxoethyl]carbamate; tert butyl [2 [[(4' aminobiphenyl 3 yl)methyl](methyl)amino]2 oxoethyl]carbamate; tert butyl [2 [[(4' formylbiphenyl 3 yl)methyl](methyl)amino] 2 oxoethyl]carbamate; unclassified drug; unindexed drug; vascular adhesion protein 1 inhibitor; acetamide derivative; amine oxidase (copper containing); AOC3 protein, human; cell adhesion molecule; glycine; vascular adhesion protein-1, rat; animal experiment; Article; chemical modification; controlled study; drug efficacy; drug penetration; drug potency; drug stability; drug synthesis; IC50; male; maximum plasma concentration; molecular model; nonhuman; rat; structure activity relation; analogs and derivatives; animal; antagonists and inhibitors; CHO cell line; Cricetulus; enzyme assay; human; molecular docking; structure activity relation; synthesis; Acetamides; Amine Oxidase (Copper-Containing); Animals; Cell Adhesion Molecules; CHO Cells; Cricetulus; Drug Stability; Enzyme Assays; Glycine; Humans; Molecular Docking Simulation; Rats; Structure-Activity Relationship