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Cinnoline Derivatives as Human Neutrophil Elastase Inhibitors

Cinnoline Derivatives as Human Neutrophil Elastase Inhibitors

Maria Paola Giovannoni, Igor A Schepetkin, Letizia Crocetti, Giovanna Ciciani, Agostino Cilibrizzi, Gabriella Guerrini, Andrei I Khlebnikov, Mark T Quinn, Claudia Vergelli

J Enzyme Inhib Med Chem. 2016 Aug;31(4):628-39.

PMID: 26194018

Abstract:

Compounds that can effectively inhibit the proteolytic activity of human neutrophil elastase (HNE) represent promising therapeutics for treatment of inflammatory diseases. We present here the synthesis, structure-activity relationship analysis, and biological evaluation of a new series of HNE inhibitors with a cinnoline scaffold. These compounds exhibited HNE inhibitory activity but had lower potency compared to N-benzoylindazoles previously reported by us. On the other hand, they exhibited increased stability in aqueous solution. The most potent compound, 18a, had a good balance between HNE inhibitory activity (IC50 value = 56 nM) and chemical stability (t1/2 = 114 min). Analysis of reaction kinetics revealed that these cinnoline derivatives were reversible competitive inhibitors of HNE. Furthermore, molecular docking studies of the active products into the HNE binding site revealed two types of HNE inhibitors: molecules with cinnolin-4(1H)-one scaffold, which were attacked by the HNE Ser195 hydroxyl group at the amido moiety, and cinnoline derivatives containing an ester function at C-4, which is the point of attack of Ser195.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP9004062	Elastase, Human Neutrophil		9004-06-2	Price

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