Dataset Information

Synthesis and Pharmacological Evaluation of Indole Derivatives as Deaza Analogues of Potent Human Neutrophil Elastase Inhibitors.

ABSTRACT: Preclinical Research A number of N-benzoylindoles were designed and synthesized as deaza analogs of previously reported potent and selective HNE inhibitors with an indazole scaffold. The new compounds containing substituents and functions that were most active in the previous series were active in the micromolar range (the most potent had IC50 ?=?3.8 ?M) or inactive. These results demonstrated the importance of N-2 in the indazole nucleus. Docking studies performed on several compounds containing the same substituents but with an indole or an indazole scaffold, respectively, highlight interesting aspects concerning the molecule orientation and H-bonding interactions, which could help to explain the lower activity of this new series. Drug Dev Res, 2016. ??© 2016 Wiley Periodicals, Inc.

SUBMITTER: Crocetti L

PROVIDER: S-EPMC5062748 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Synthesis and Pharmacological Evaluation of Indole Derivatives as Deaza Analogues of Potent Human Neutrophil Elastase Inhibitors.

Crocetti Letizia L Schepetkin Igor A IA Ciciani Giovanna G Giovannoni Maria Paola MP Guerrini Gabriella G Iacovone Antonella A Khlebnikov Andrei I AI Kirpotina Liliya N LN Quinn Mark T MT Vergelli Claudia C

Drug development research 20160730 6

Preclinical Research A number of N-benzoylindoles were designed and synthesized as deaza analogs of previously reported potent and selective HNE inhibitors with an indazole scaffold. The new compounds containing substituents and functions that were most active in the previous series were active in the micromolar range (the most potent had IC50 = 3.8 μM) or inactive. These results demonstrated the importance of N-2 in the indazole nucleus. Docking studies performed on several compounds containin ...[more]

PMID: 27474878

Similar Datasets

Project description:Human neutrophil elastase (HNE) is a serine protease that plays vital roles in inflammation, innate immune response, and tissue remodeling processes. HNE has been actively pursued as a drug target, particularly for the treatment of cardiopulmonary diseases. Although thousands of molecules have been reported to inhibit HNE, yet very few are being evaluated in early clinical trials, with sivelestat as the only approved HNE inhibitor. We report here a novel chemotype of sulfonated nonsaccharide heparin mimetics as potent and noncompetitive inhibitors of HNE. Using a chromogenic substrate hydrolysis assay, 14 sulfonated nonsaccharide heparin mimetics were tested for their inhibitory activity against HNE. Only 12 molecules inhibited HNE with IC50 values of 0.22-88.3 μM. The inhibition of HNE by these molecules was salt-dependent. Interestingly, a specific hexa-sulfonated molecule inhibited HNE with an IC50 value of 0.22 μM via noncompetitive mechanism, as demonstrated by Michaelis-Menten kinetics. The hexa-sulfonated derivative demonstrated at least 455-, 221-, 1590-, 21-, and 381-fold selectivity indices over other heparin-binding coagulation proteins including factors IIa, Xa, IXa, XIa, and FXIIIa, respectively. At the highest concentrations tested, the molecule also did not significantly inhibit other serine proteases of plasmin, trypsin, and chymotrypsin. Further supporting its selectivity, the molecule did not show heparin-like effects on clotting times of human plasma. The molecule also did not affect the proliferation of three cell lines at a concentration as high as 10 μM. Interestingly, the hexa-sulfonated molecule also inhibited cathepsin G with an IC50 value of 0.57 μM alluding to a dual anti-inflammatory action. A computational approach was exploited to identify putative binding site(s) for this novel class of HNE inhibitors. Overall, the reported hexa-sulfonated nonsaccharide heparin mimetic serves as a new platform to develop potent, selective, and noncompetitive inhibitors of HNE for therapeutic purposes.

Dataset Information

Synthesis and Pharmacological Evaluation of Indole Derivatives as Deaza Analogues of Potent Human Neutrophil Elastase Inhibitors.

Publications

Synthesis and Pharmacological Evaluation of Indole Derivatives as Deaza Analogues of Potent Human Neutrophil Elastase Inhibitors.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets