Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0034067 (emphysema)
 11,506 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human leukocyte elastase (HLE) is a serine protease produced by neutrophils that has been implicated in diseases such as emphysema and cystic fibrosis. An HLE inhibitor may have therapeutic value in these diseases. An active site model of HLE bound to a tripeptidic trifluoromethyl ketone (TFMK) inhibitor, 2, was created from X-ray structures of HLE and porcine pancreatic elastase. Analysis of the model indicated a preferred binding conformation for the tripeptide and potentially important interactions between it and the enzyme. This information was used to aid in the design of a series of novel, pyridone-containing, non-peptidic HLE inhibitors such as 2-[3-[[(benzyloxy)carbonyl]amino]-2-oxo- 1,2-dihydro-1-pyridyl]-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)ace tam ide (5b) (Ki = 280 +/- 78 nM). Inspection of the active site model suggested that a benzyl substituent at the 5-position of the pyridone ring might improve potency by forming a lipophilic interaction with the enzyme S2 pocket. Synthesis and biological evaluation of a series of 5-benzylpyridone TFMKs provided evidence for this proposition. Further analysis of the model indicated that substitution on the 3-amino group of the pyridone ring with a hydrogen bond acceptor could potentially lead to interactions with the NH atoms of glycine-218 and/or -219. The oxalate derivative 2-[5-benzyl- 3-(carboxycarbonyl)-2-oxo-1,2-dihydro-1-pyridyl]-N-(3,3,3-trifl uor o-1- isopropyl-2-oxopropyl)acetamide (5v) was synthesized and found to have a Ki of 48 +/- 9 nM. Unfortunately, none of the compounds tested was active in an in vivo model of HLE-induced lung injury when dosed orally.
 ...
PMID:Non-peptidic inhibitors of human leukocyte elastase. 1. The design and synthesis of pyridone-containing inhibitors. 793 32

A method which will reduce significantly the viscosity of epithelial mucus is essential to the physiological mechanisms involved in the mobilization and removal of such secretions. The life expectancy of patients with chronic pulmonary conditions and cystic fibrosis has been considerably increased and consequently the problem of liquefying mucin acquires new importance. In view of these considerations, as well as to facilitate research into the structural relationship of the glycoprotein macromolecule, a systematic investigation of mucolysis was undertaken using gastric mucin. Three amides, carbamide, acetamide and formamide, were found to dissolve gastric gel mucin with minimal degradation, and rapidly disperse the viscous secretions produced in pathological conditions of the tracheobronchial tree. Their effect on secretions from patients with cystic fibrosis and bronchiectasis is dramatic, and within five minutes of adding the reagent the flow time was reduced by at least 95%. Clinical studies were carried out with carbamide (urea in anhydrous, lyophilized, sterile powder form) in 32 patients with a variety of bronchial conditions, including chronic bronchitis, cystic fibrosis, asthma, bronchiectasis and emphysema. With the concentrations used, no irritant, bronchospastic or other reactions were observed.IT IS CONCLUDED THAT AMIDES OF THIS TYPE HAVE AT LEAST TWO ACTIONS ON THE EPITHELIAL MUCOUS SECRETION: (1) breakage of the three-dimensional gel structure and (2) a slower reduction in viscosity followed by solution of the solid material.
 ...
PMID:The mucolytic activity of amides: a new approach to mucus dispersion. 2032 63