Document Detail

Orally bioavailable benzisothiazolone inhibitors of human leukocyte elastase.
MedLine Citation:
PMID:  7877139     Owner:  NLM     Status:  MEDLINE    
Human leukocyte elastase (HLE) has been proposed as a primary mediator of pulmonary emphysema and other inflammatory airway diseases. HLE is capable of cleaving many proteins, including elastin, other components of connective tissue, certain complement proteins, and receptors. Under normal conditions an appropriate balance exists in the lung between HLE and endogenous inhibitors, which scavenge the released enzyme before it exerts deleterious effects in the lung. Emphysema is thought to result from an imbalance in the lung between HLE and endogenous inhibitor (elevated elastase or insufficient inhibitor) that leads to the destruction of alveoli. We have identified WIN 64733 (2) and WIN 63759 (3) as potent (Ki* = 14 and 13 pM, respectively), selective, mechanism-based inhibitors of HLE which are orally bioavailable in the dog (absolute bioavailability 46% and 21%, respectively). In this series the in vitro stabilities of the inhibitors in blood, jejunal homogenates, and liver S9 homogenates are useful predictors of oral bioavailability. After being administered orally (30 mg/kg) to dogs, compounds 2 and 3 are found in the lung, being detected in the epithelial lining fluid obtained by bronchoalveolar lavage (Cmax of 2.5 and 0.47 microgram/mL, respectively).
D J Hlasta; C Subramanyam; M R Bell; P M Carabateas; J J Court; R C Desai; M L Drozd; W M Eickhoff; E W Ferguson; R J Gordon
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Publication Detail:
Type:  In Vitro; Journal Article    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  38     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  1995 Mar 
Date Detail:
Created Date:  1995-04-04     Completed Date:  1995-04-04     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  739-44     Citation Subset:  IM    
Department of Medicinal Chemistry, Sterling Winthrop Inc., Collegeville, Pennsylvania 19426.
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MeSH Terms
Administration, Oral
Biological Availability
Chlorobenzoates / chemical synthesis,  pharmacokinetics,  pharmacology
Drug Stability
Leukocyte Elastase
Lung / enzymology,  metabolism
Macaca fascicularis
Pancreatic Elastase / antagonists & inhibitors*
Rats, Sprague-Dawley
Thiazoles / chemical synthesis*,  pharmacokinetics,  pharmacology*
Reg. No./Substance:
0/Chlorobenzoates; 0/Thiazoles; 2634-33-5/1,2-benzisothiazoline-3-one; EC Elastase; EC Elastase

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