Chronic obstructive pulmonary disease (COPD), a disease characterized by airflow obstruction due to chronic bronchitis and emphysema, affects more than 16 million Americans and is currently the fourth most common cause of death. COPD is continuing to increase in both prevalence and mortality, with the cost of care estimated to be approximately $24 billion/yr. It is generally accepted that COPD is a multifactorial disease the pathophysiology of which is associated with in influx of neutrophils and other phagocytic cells to the lungs, and the subsequent release of an array of proteases, leading to an imbalance between the levels of the proteases and their endogenous protein inhibitors. This imbalance results in poor regulation of the activity of these enzymes, which then degrade the major components of the extracellular matrix, ultimately leading to the onset of disease. It is hypothesized herein that agents capable of regulating selectively the activity of the renegade enzymes, thereby re-establishing a protease-antiprotease balance, are of value as probes for delineating the precise role of a particular protease in COPD, and as potential therapeutic agents. Thus, the specific aims of the proposed research are (a) structure-based design and synthesis of selective inhibitors of various proteases implicated in COPD based on an array of heterocyclic scaffolds.
This aim i ncludes the formulation and validation of a general strategy related to the design of selective inhibitors of (chymo)trypsin-like mammalian, viral and bacterial proteases; (b) structure-based design and synthesis of two novel and general classes of inhibitors of serine, cysteine and metallo-proteases; (c) design of a novel class of mechanism-based inhibitors of serine proteases that are postulated to inactivate a target enzyme via an unprecedented enzyme-induced 3-aza Grob fragmentation process and, (d) biochemical and structural studies aimed at determining the inhibitory activity, enzyme selectivity and mechanism of action of the inhibitors.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL057788-06
Application #
6621192
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Program Officer
Croxton, Thomas
Project Start
1997-12-10
Project End
2005-11-30
Budget Start
2002-12-01
Budget End
2003-11-30
Support Year
6
Fiscal Year
2003
Total Cost
$178,820
Indirect Cost
Name
Wichita State University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
053078127
City
Wichita
State
KS
Country
United States
Zip Code
67260
Dou, Dengfeng; He, Guijia; Alliston, Kevin R et al. (2011) Dual function inhibitors of relevance to chronic obstructive pulmonary disease. Bioorg Med Chem Lett 21:3177-80
Groutas, William C; Dou, Dengfeng; Alliston, Kevin R (2011) Neutrophil elastase inhibitors. Expert Opin Ther Pat 21:339-54
Dou, Dengfeng; Viwanathan, Prasanth; Li, Yi et al. (2010) Design, synthesis, and in vitro evaluation of potential West Nile virus protease inhibitors based on the 1-oxo-1,2,3,4-tetrahydroisoquinoline and 1-oxo-1,2-dihydroisoquinoline scaffolds. J Comb Chem 12:836-43
He, Guijia; Dou, Dengfeng; Wei, Liuqing et al. (2010) Inhibitors of human neutrophil elastase based on a highly functionalized N-amino-4-imidazolidinone scaffold. Eur J Med Chem 45:4280-7
Dou, Dengfeng; He, Guijia; Kuang, Rongze et al. (2010) Effects of structure on inhibitory activity in a series of mechanism-based inhibitors of human neutrophil elastase. Bioorg Med Chem 18:6646-50
Dou, Dengfeng; He, Guijia; Li, Yi et al. (2010) Utilization of the 1,2,3,5-thiatriazolidin-3-one 1,1-dioxide scaffold in the design of potential inhibitors of human neutrophil proteinase 3. Bioorg Med Chem 18:1093-102
Li, Yi; Dou, Dengfeng; He, Guijia et al. (2009) Mechanism-based inhibitors of serine proteases with high selectivity through optimization of S' subsite binding. Bioorg Med Chem 17:3536-42
Yang, Qingliang; Li, Yi; Dou, Dengfeng et al. (2008) Inhibition of serine proteases by a new class of cyclosulfamide-based carbamylating agents. Arch Biochem Biophys 475:115-20
Huang, Weijun; Yamamoto, Yasufumi; Li, Yi et al. (2008) X-ray snapshot of the mechanism of inactivation of human neutrophil elastase by 1,2,5-thiadiazolidin-3-one 1,1-dioxide derivatives. J Med Chem 51:2003-8
Li, Yi; Yang, Qingliang; Dou, Dengfeng et al. (2008) Inactivation of human neutrophil elastase by 1,2,5-thiadiazolidin-3-one 1,1 dioxide-based sulfonamides. Bioorg Med Chem 16:692-8

Showing the most recent 10 out of 24 publications