PMN elastases: A comparison of the specificity of human isozymes and the enzyme from other species toward substrates and inhibitors

Green, B.G.; Weston, Hazel; Ashe, Bonnie M.; Doherty, James B.; Finke, Paul E.; Hagmann, William K.; Lark, Michael W.; Mao, Jennifer; Maycock, Alan L.; Moore, Vernon L.; Mumford, Richard A.; Shah, Shrenik K.; Walakovits, Lori A.; Knight, Wilson B.

doi:10.1016/0003-9861(91)90042-h

Cited by 34 publications

(28 citation statements)

References 29 publications

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“…In another example, inactivation of PMNE by 13 liberated p-nitrophenol, implying once again that the C4 substituent is not present in the stable E-I complex. These results represented a significant improvement over the partitioning of E-I complexes produced from the cephalosporins (13,24) and simple f3-lactams (25). Because the C-4 substituent is not present, the stability of the final E-I complexes depended only on the identity ofthe urea moiety.…”

Section: Synthesimentioning

confidence: 73%

“…Preparation of the optical isomers of 6 showed that essentially all inhibitory activity resided in the enantiomer depicted in Fig. 1 (13,14). Compound 7 was significantly more stable than 6 (-20-fold) but was found to be very weakly active against PMNE.…”

Section: Synthesimentioning

confidence: 99%

“…This activity is reflected functionally by inhibition of human PMNE-mediated lung injury in the hamster and the inhibition of this enzyme released from human PMN transferred into the pleural cavity of mice. (13). The presence of these (3-lactam inhibitors in the activity assay resulted in a pseudo-first-order loss of PMNE activity with time.…”

mentioning

confidence: 99%

“…The presence of these (3-lactam inhibitors in the activity assay resulted in a pseudo-first-order loss of PMNE activity with time. The second-order rate constants (kinactivation/Ki) for the inactivation ofPMNE by inhibitors were determined from these progress curves (13,14).…”

mentioning

confidence: 99%

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Chemical, biochemical, pharmacokinetic, and biological properties of L-680,833: a potent, orally active monocyclic beta-lactam inhibitor of human polymorphonuclear leukocyte elastase.

Doherty

Shah

Finke

et al. 1993

Proc. Natl. Acad. Sci. U.S.A.

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A series of potent and highly selective dimedependent monocyclic J-lactaminhibitors of human polymorphonuclear leukocyte elastas (PMNE, EC 3.4.21.37 and potency for PMNE but suffer from the drawbacks ofpoor oral bioavailability and modest stability in plasma, minimizing their potential value as systemically administered therapeutic agents. Given the constraints imposed by the structure of the cephem nucleus on the substitution pattern of the ,B-lactam ring, it was considered that the monocyclic f-lactam nucleus could be optimized for each substituent attached to it, leading to the optimum balance between intrinsic chemical stability, potency toward PMNE, and specificity against other serine proteases. We now report on the properties of a Fig. 1). This compound shows potent, time-dependent inhibition of human PMNE, possesses a high degree of selectivity against other serine proteases, and inhibits the activity of PMNE released from stimulated PMN. It exhibits good oral bioavailability in rats and rhesus monkeys. This activity is reflected functionally by inhibition of human PMNE-mediated lung injury in the hamster and the inhibition of this enzyme released from human PMN transferred into the pleural cavity of mice.

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Section: Synthesimentioning

confidence: 73%

Section: Synthesimentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Chemical, biochemical, pharmacokinetic, and biological properties of L-680,833: a potent, orally active monocyclic beta-lactam inhibitor of human polymorphonuclear leukocyte elastase.

Doherty

Shah

Finke

et al. 1993

Proc. Natl. Acad. Sci. U.S.A.

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“…Human leukocyte elastase. Human sputum elastase was used as human leukocyte elastase (Green et al, 1991). The enzyme was dissolved in assay buffer (50 mM HEPES/NaOH, pH 7.8, containing 0.5 M NaCl and 0.1 mg/ml bovine serum albumin) at a 656 U/ml (30 M) concentration.…”

Section: In Vitro Studiesmentioning

confidence: 99%

Biochemical and Pharmacological Characterization of 2-(9-(2-Piperidinoethoxy)-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yloxymethyl)-4-(1-methylethyl)-6-methoxy-1,2-benzisothiazol-3(2H)-one-1,1-dioxide (SSR69071), a Novel, Orally Active Elastase Inhibitor

Kapui¹,

Varga²,

Urban-Szabo³

et al. 2003

J Pharmacol Exp Ther

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Synthetic Inhibitors of Elastase

Edwards

Bernstein

1994

Medicinal Research Reviews

215

156

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For more than two decades investigators around the world, in both academic and industrial institutions, have been developing inhibitors of human neutrophil elastase. A number of very elegant and insightful strategies have been reported. In the case of reversible peptidic inhibitors, this has resulted in the identification of some extremely potent compounds with dissociation constants in the 10(-11) M range. This is quite an accomplishment considering that these low molecular-weight inhibitors are only tri- and tetrapeptides. In the case of the heterocyclic-based inhibitors, the challenge of balancing the heterocycle's inherent reactivity and aqueous stability with the stability of the enzyme-inhibitor adduct has been meet by either using a latent, reactive functionality which is only activated within the enzyme, or by incorporating features which selectively obstruct deacylation but have little effect on the enzyme acylation step. The underlying goal of this research has been the identification of agents to treat diseases associated with HNE. Several animal models have been developed for evaluating the in vivo activity of elastase inhibitors, and compounds have been shown to be effective in all of these models by the intravenous, intratrachael or oral routes of administration. However, only a very small percentage of compounds have possessed all the necessary properties, including lack of toxicity, for progression into the clinic. The peptidyl TFMK ICI 200,880 (25-12) has many of the desired characteristics of a drug to treat the diseases associated with HNE: chemical stability, in vitro and in vivo activity, a long duration of action, and adequate metabolic stability. Currently ICI 200,880 is the only low molecular-weight HNE inhibitor known to be undergoing clinical trials, and may be the compound which finally demonstrates the clinical utility of a synthetic HNE inhibitor.

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PMN elastases: A comparison of the specificity of human isozymes and the enzyme from other species toward substrates and inhibitors

Cited by 34 publications

References 29 publications

Chemical, biochemical, pharmacokinetic, and biological properties of L-680,833: a potent, orally active monocyclic beta-lactam inhibitor of human polymorphonuclear leukocyte elastase.

Chemical, biochemical, pharmacokinetic, and biological properties of L-680,833: a potent, orally active monocyclic beta-lactam inhibitor of human polymorphonuclear leukocyte elastase.

Biochemical and Pharmacological Characterization of 2-(9-(2-Piperidinoethoxy)-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yloxymethyl)-4-(1-methylethyl)-6-methoxy-1,2-benzisothiazol-3(2H)-one-1,1-dioxide (SSR69071), a Novel, Orally Active Elastase Inhibitor

Synthetic Inhibitors of Elastase

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