title: Synthesis and pharmacological characterization of 2-aminobenzaldehyde oxime analogs as dual inhibitors of neutrophil elastase and proteinase 3.
abstract: Proteinase 3 (Pr3), and human neutrophil elastase (HNE) are two major neutrophilic serine proteases (NsPs) expressed in neutrophil azurophil granules. Emerging data suggest that excessive release of proteases mediates tissue damage, and therefore prolonged neutrophil accumulation has an important role in the pathogenesis of many diseases. Thus, HNE and Pr3 inhibitors may prove to be targets for the generation of agents in the treatment of neutrophilic inflammatory disease. Sivelestat is the only commercially available selective HNE inhibitor. Therefore, sivelestat was chosen as the model structure in an attempt to obtain more potent anti-NsPs agents. In the present study, a series 2-aminobenzaldehyde oxime and 2-aminobenzoate analogs were synthesized and their inhibitory effects on NsPs (CatG, Pr3, and HNE) were determined, respectively. The results of structure-activity relationships studies concluded that a hydroxyl oxime moiety plays an important role in ligand-enzyme affinity through hydrogen bonding. As compound 6 had more potency and showed dual inhibitory effects on NE and Pr3, both in vitro and in vivo experiments were carried out to evaluate its selectivity, effects in cell-based assays, and efficacy in models of inflammation and damage. Compound 6 had the potential to reduce paw edema induced by LPS and HNE, as well as acute lung injury, and may be approved as a candidate for the development of new agents in the treatment of neutrophilic inflammatory diseases.
authors: Graduate Institute of Natural Products, School of Traditional Chinese Medicine, and Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan; Research Center for Industry of Human Ecology, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan.
authors: Tsong-Long
authors: TL
authors: Hwang
authors: Graduate Institute of Natural Products, School of Traditional Chinese Medicine, and Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.
authors: Wen-Hui
authors: WH
authors: Wang
authors: Graduate Institute of Natural Products, School of Traditional Chinese Medicine, and Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.
authors: Ting-Yi
authors: TY
authors: Wang
authors: Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; School Medicine, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.
authors: Huang-Ping
authors: HP
authors: Yu
authors: Graduate Institute of Natural Products, School of Traditional Chinese Medicine, and Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan; Research Center for Industry of Human Ecology, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan. Electronic address: pewehs@mail.cgu.edu.tw.
authors: Pei-Wen
authors: PW
authors: Hsieh
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000201:enzymology; D000818:Animals; D001547:Benzaldehydes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004487:Edema / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D053146:Myeloblastin / Q000037:antagonists & inhibitors*; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D010091:Oximes / Q000737:chemistry; D009195:Peroxidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D013481:Superoxides / Q000378:metabolism
chemical_list: D001547:Benzaldehydes; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D010091:Oximes; D013481:Superoxides; C000062:2-aminobenzaldehyde; D009195:Peroxidase; D019272:Leukocyte Elastase; D053146:Myeloblastin
keywords: 2-Aminobenzaldehyde oxime analogs; Acute lung injury; Neutrophil elastase; Proteinase 3