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 mgkg) to dogs, compounds 2 and 3 are found in the lung, being detected in the epithelial lining fluid obtained by bronchoalveolar lavage (C,,, of 2.5 and 0.47 pg/mL, respectively).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 receptorsa2 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. In response to inflammatory mediators, HLE and other proteases are released from the granules of neutrophils. An imbalance between HLE and endogenous inhibitory
We conclude that SR233377 administered on a 5-day schedule is associated with tolerable clinical symptoms and some activity against a range of solid tumors but dosing is limited by QTc prolongation, a condition that predisposes to ventricular arrhythmias. Phase II development on this schedule is not recommended based on the occurrence of this concentration-dependent effect. Further investigation of alternative schedules of administration and of SR233377 analogues is warranted.
Supported by the antiherpetic properties of 3-quinolinecarboxamides and the importance of the planar intramolecular H-bonded beta-keto amide pharmacophore, a series of novel conformationally rigid analogues that contain a heterocyclic bridge between the 3- and 4-positions of the quinoline ring have been evaluated. Two isoxazolo-fused derivatives 17 and 23 displayed good in vitro antiherpetic potency that was similar to that of 1, the 3-quinolinecarboxamide that served as the comparison structure for this study. The pyrazolo, pyrrolo, and pyrimido derivatives showed considerably less or no activity. In vitro activity did not translate to in vivo efficacy. For 17, the lack of in vivo activity is likely a consequence of insufficient plasma drug levels (both Cmax and duration) in mice relative to the MIC versus HSV-2.
The proteolytic activity of human neutrophil elastase (HNE) has been implicated in a number of pulmonary diseases. We report on the activity of an orally bioavailable, selective HNE inhibitor, WIN 63759 [6-rnethoxy-4-(1-methylethy)-3-oxo-l,2-benzisothiazol-2(3H)-yl]methyl 2,6dichloro-3-[2-(4-morpholinyl)ethoxy] benzoate S,S dioxide. WIN 63759 is a potent inhibitor of HNE (K, = 14 pM) and is at least 70,000-fold selective for HNE relative to other serine proteases or receptors. In vivo, WIN 63759 produces dose-related inhibition of HNE-induced pulmonary hemorrhage following either intravenous ( ED, , = 3 mgikg; 4.5 kmol/kg) or subcutaneous ( ED, , = 19 mgikg; 28.5 prnolikg) administration in hamsters. WIN 63759 selectivity inhibits HNE In vivo (relative to chymotrypsin or trypsin), and is equally efficacious following acute or chronic administration in the hamster. WIN 63759 is not orally bioavailable in hamsters, rats, or monkeys, and this lack of bioavailability is related to rapid in vitro metabolism in liver, jejunum, or blood. In contrast, WIN 63759 i s stable in canine tissues in vitro and i s orally bioavailable in dogs. Bioavailability i s enhanced in fed relative to fasted dogs. Bronchoalveolar lavage studies indicate that WIN 63759 is present in the target organ (lung) at concentrations 3-5 x higher than those found in plasma following oral administration of 3-100 mgikg (4.5-150 pmol) in dogs. These data show that WIN 63759 i s a potent, selective, and orally bioavailable inhibitor of HNE. Since oral bioavailability was predictable based on in vitro metabolism, and since in vitro metabolism in humans i s similar to that observed with dogs, WIN 63759 and other members of this chemical series may be orally bioavailable inhibitors of neutrophil elastase in man. o 1995 Wiley-Liss, Inc
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