The chemistry and biological potential of azetidin-2-ones.

Pyridyl esters of 6-substituted 2-oxo-2H-1-benzopyran-3-carboxylic acid were designed as mechanism-based inhibitors of human leukocyte elastase. Compounds of series 4 specifically inhibited this enzyme. Several of the tested compounds (series 2 and 3) acted as powerful time-dependent inhibitors of both human leukocyte elastase and α-chymotrypsin; some compounds of these series inhibited thrombin. Trypsin was not inhibited. A transient inactivation was observed for human leukocyte elastase (ki/KI = 107 000 M-1·s-1 for 4c) and thrombin (ki/KI = 7 200 M-1·s-1 for 3b) as demonstrated by spontaneous or hydroxylamine-accelerated reactivation, irrespective of the nature of the substituent at the 6-position. Conversely, α-chymotrypsin was irreversibly inhibited by 6-chloromethyl derivatives (ki/KI = 107 400 M-1·s-1 for 3b). The presence of a latent alkylating function at the 6-position (chloromethyl group) was required for leading to this inactivation. In the absence of such an alkylating function (series 4), hum...

6-Substituted 2-oxo-2H-1-benzopyran-3-carboxylic acid as a core structure for specific inhibitors of human leukocyte elastase.

Human neutrophil elastase (NE) plays an important role in the pathogenesis of pulmonary disease. Using high-throughput chemolibrary screening, we identified 10 N-benzoylpyrazole derivatives that were potent NE inhibitors. Nine additional NE inhibitors were identified through further screening of N-benzoylpyrazole analogues. Evaluation of inhibitory activity against a range of proteases showed high specificity for NE, although several derivatives were also potent inhibitors of chymotrypsin. Analysis of reaction kinetics and inhibitor stability revealed that N-benzoylpyrazoles were pseudoirreversible competitive inhibitors of NE. Structure-activity relationship (SAR) analysis demonstrated that modification of N-benzoylpyrazole ring substituents modulated enzyme selectivity and potency. Furthermore, molecular modeling of the binding of selected active and inactive compounds to the NE active site revealed that active compounds fit well into the catalytic site, whereas inactive derivatives contained substituents or conformations that hindered binding or accessibility to the catalytic residues. Thus, N-benzoylpyrazole derivatives represent novel structural templates that can be utilized for further development of efficacious NE inhibitors.

N-Benzoylpyrazoles Are Novel Small-Molecule Inhibitors of Human Neutrophil Elastase

Synthesis and evaluation of N1/C4-substituted beta-lactams as PPE and HLE inhibitors.

Human neutrophil elastase (HNE) is an important therapeutic target for treatment of pulmonary diseases. Previously, we identified novel N-benzoylindazole derivatives as potent, competitive, and pseudoirreversible HNE inhibitors. Here, we report further development of these inhibitors with improved potency, protease selectivity, and stability compared to our previous leads. Introduction of a variety of substituents at position 5 of the indazole resulted in the potent inhibitor 20f (IC50 ∼10 nM) and modifications at position 3 resulted the most potent compound in this series, the 3-CN derivative 5b (IC50 = 7 nM); both derivatives demonstrated good stability and specificity for HNE versus other serine proteases. Molecular docking of selected N-benzoylindazoles into the HNE binding domain suggested that inhibitory activity depended on geometry of the ligand–enzyme complexes. Indeed, the ability of a ligand to form a Michaelis complex and favorable conditions for proton transfer between Hys57, Asp102, and Ser1...

/pdf/optimization-of-n-benzoylindazole-derivatives-as-inhibitors-ug8zdbftxk.pdf

Optimization of N-Benzoylindazole Derivatives as Inhibitors of Human Neutrophil Elastase

Interaction of human leukocyte elastase with a N-aryl azetidinone suicide substrate: Conformational analyses based on the mechanism of action of serine proteinases.

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Interaction of human leukocyte elastase with a N-aryl azetidinone suicide substrate: Conformational analyses based on the mechanism of action of serine proteinases.