Pharmacological profile of the substituted beta‐lactam L‐659,286: A member of a new class of human PMN elastase inhibitors

  title={Pharmacological profile of the substituted beta‐lactam L‐659,286: A member of a new class of human PMN elastase inhibitors},
  author={Robert J. Bonney and Bonnie M. Ashe and Alan L. Maycock and Pam S. Dellea and K M Hand and Donald G. Osinga and Daniel S. Fletcher and Richard A. Mumford and Philip Davies and D. Frankenfield and Thomas E. Nolan and Laurent Schaeffer and William K. Hagmann and Paul E. Finke and S. Shah and C. P. Jun. Dorn and James Doherty},
  journal={Journal of Cellular Biochemistry},
Human polymorphonuclear leukocyte elastase (PMN elastase) is inhibited by L‐659, 286 (7α‐methoxy‐8‐oxo‐3‐[[(1,2,5,6‐tetrahydro‐2‐methyl‐5,6‐dioxo‐1,2,4‐triaz‐in‐3‐yl)thio]methyl]‐5‐thia‐1‐aza‐6R‐bicyclo [4.2.O]oct‐2‐ene‐2‐pyrrolidine carboxamide‐5,‐dioxide) with a Ki of 0.4 μM. This inhibition is time‐dependent, rapid, and only slowly reversible, with a t1/2 of > 3 days at 25°C. L‐659, 286 is also highly selective for PMN elastase, as it does not inhibit thrombin, trypsin, papain, plasmin… 

Biological activity of WIN 63759, an orally bioavailable inhibitor of human neutrophil elastase

Data show that WIN 63759 is a potent, selective, and orally bioavailable inhibitor of HNE, and other members of this chemical series may be orally bio available inhibitors of neutrophil elastase in man.

Specificity, stability, and potency of monocyclic beta-lactam inhibitors of human leucocyte elastase.

Differences in the structure-activity relationships of the human versus the rat enzymes suggest significant differences between these two functionally similar enzymes that suggest that the alkyl substitutions at C-3 of the lactam ring bind in the S1 specificity pocket of these enzymes.

Biochemical and pharmacological characterization of FK706, a novel elastase inhibitor.

Biochemical and pharmacological characterization of ICI 186,756: a novel, potent, and selective inhibitor of human neutrophil elastase.

It is concluded that ICI 186,756 is a potent, competitive, and selective inhibitor of HNE that may be useful in understanding the role of this enzyme in animal models of various diseases.

Biochemistry and Pharmacology of ICI 200,880, a Synthetic Peptide Inhibitor of Human Neutrophil Elastase

It is concluded that ICI 200,880 has biochemical, pharmacokinetic, and pharmacologic profiles that make it a useful therapeutic agent for understanding the role of HNE in various diseases.

The Discovery and Biologic Properties of Cephalosporin‐Based Inhibitors of PMN Elastase

A failure to maintain normal levels of elastase and cathepsin G in mature PMNs in the beige mousezo has been described which may be due to inactivation of enzyme by inhibitors present.

Inhibitors directed to binding domains in neutrophil elastase.

It is shown that the interaction of oleic acid with HNE can be characterized by two apparent inhibitory modes: a high-affinity mode, resulting in partial noncompetitive inhibition, and a competitive inhibitory mode of lower affinity, which induces a blue shift in the endogenous fluorescence arising from the tryptophan residues in HNE.



Reaction of serine proteases with substituted isocoumarins: discovery of 3,4-dichloroisocoumarin, a new general mechanism based serine protease inhibitor.

3,4-Dichloroisocoumarin, the most potent inhibitor investigated here, inactivated all the serine proteases tested but did not inhibit papain, leucine aminopeptidase, or beta-lactamase.

Cephalosporin antibiotics can be modified to inhibit human leukocyte elastase

It is reported that neutral cephalosporins (that is, compounds not bearing a free carboxyl at position C-4) can be modified to become potent time-dependent inhibitors of HLE.

Mechanism of inactivation of human leukocyte elastase by a chloromethyl ketone: kinetic and solvent isotope effect studies.

The mechanism of inactivation of human leukocyte elastase by the chloromethyl ketone MeOSuc-Ala-AlA-Pro-Val-CH/sub 2/Cl was investigated and it is proposed that this second complex is a hemiketal formed from attack of the active site serine on the carbonyl carbon of the inhibitor.

Purification and characterization of two human pancreatic elastases.

Two proteases with elastolytic activity (elastases 1 and 2) have been isolated from activated extracts of human pancreatic tissue and characterized in terms of molecular weight, amino acid composition, and N-terminal and penultimate amino acid residues.

Natural history and life expectancy in severe alpha1-antitrypsin deficiency, Pi Z.

  • C. Larsson
  • Medicine, Biology
    Acta medica Scandinavica
  • 1978
Smokers with severe alpha1-antitrypsin deficiency, Pi Z, had a significantly lower life expectancy than non-smokers and a greatly reduced survival, regardless of sex.

Inspiratory and expiratory partitioning of airway resistance during sleep in patients with sleep apnea.

It is concluded that airway abnormalities occur during both the expiratory and the inspiratory phases of ventilation on breath(s) leading to apnea and, therefore, the loss of airway patency is not solely an inspiratory phenomenon.