Pulmonary emphysema is currently believed to accrue as a result of a proteinase/proteinase inhibitor imbalance in the lungs. The proteinases that are believed to be primarily responsible for the degradation of lung connective tissue are neutrophil elastase and cathepsin G. Other neutrophil enzymes that play a role in the disease are proteinase-3, cathepsin L, and myeloperoxidase. The long-term goal of the proposed research is the elucidation of the biochemical basis underlying pulmonary emphysema and the development of effective therapeutic interventions through the modulation of the activity of the enzymes implicated in the pathogenesis of the disease. The specific objectives of the proposed research are the following: a) the biochemically-based design and synthesis of inhibitors of the serine proteases leukocyte elastase, cathepsin G and proteinase-3. The design of the inhibitors is based on the Lossen and Gabriel-Colman rearrangements and will be aided by molecular graphics and modeling. b) in vitro biochemical studies aimed at determining the efficacy, mechanism of action, biospecificity and stability of the inhibitors. These studies will also include the mapping of the active site of proteinase-3 (to be done in collaboration with Dr. John Hoidal, University of Utah Health Sciences Center). c) in vivo pharmacological studies to evaluate the efficacy and toxicity of the synthesized compounds (to be done in collaboration with Dr. George Weinbaum of The Graduate Hospital, Philadelphia).

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL038048-08
Application #
2218658
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Project Start
1987-04-01
Project End
1995-06-30
Budget Start
1994-04-01
Budget End
1995-06-30
Support Year
8
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Wichita State University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
Wichita
State
KS
Country
United States
Zip Code
67260
Groutas, W C; Kuang, R; Venkataraman, R et al. (1997) Structure-based design of a general class of mechanism-based inhibitors of the serine proteinases employing a novel amino acid-derived heterocyclic scaffold. Biochemistry 36:4739-50
Groutas, W C; Epp, J B; Venkataraman, R et al. (1996) Design, synthesis, and in vitro inhibitory activity toward human leukocyte elastase, cathepsin G, and proteinase 3 of saccharin-derived sulfones and congeners. Bioorg Med Chem 4:1393-400
Groutas, W C; Chong, L S; Venkataraman, R et al. (1996) Amino acid-derived phthalimide and saccharin derivatives as inhibitors of human leukocyte elastase, cathepsin G, and proteinase 3. Arch Biochem Biophys 332:335-40
Groutas, W C; Venkataraman, R; Chong, L S et al. (1995) Isoxazoline derivatives as potential inhibitors of the proteolytic enzymes human leukocyte elastase, cathepsin G and proteinase 3: a structure-activity relationship study. Bioorg Med Chem 3:125-8
Groutas, W C; Chong, L S; Venkataraman, R et al. (1995) The Gabriel-Colman rearrangement in biological systems: design, synthesis and biological evaluation of phthalimide and saccharin derivatives as potential mechanism-based inhibitors of human leukocyte elastase, cathepsin G and proteinase 3. Bioorg Med Chem 3:187-93
Groutas, W C; Brubaker, M J; Chong, L S et al. (1995) Design, synthesis and biological evaluation of succinimide derivatives as potential mechanism-based inhibitors of human leukocyte elastase, cathepsin G and proteinase 3. Bioorg Med Chem 3:375-81
Groutas, W C; Kuang, R; Venkataraman, R (1994) Substituted 3-oxo-1,2,5-thiadiazolidine 1,1-dioxides: a new class of potential mechanism-based inhibitors of human leukocyte elastase and cathepsin G. Biochem Biophys Res Commun 198:341-9
Groutas, W C; Huang, H; Epp, J B et al. (1994) Mechanism-based inhibition of human leukocyte elastase and cathepsin G by substituted dihydrouracils. Biochim Biophys Acta 1227:130-6
Groutas, W C; Brubaker, M J; Chong, L S et al. (1994) Derivatives of 3-alkyl-N-hydroxysuccinimide: probing the effect of structure on bioactivity toward human leukocyte elastase. Drug Des Discov 11:149-57
Groutas, W C; Chong, L S; Venkataraman, R et al. (1993) Mechanism-based inhibitors of serine proteinases based on the Gabriel-Colman rearrangement. Biochem Biophys Res Commun 194:1491-9

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