1H-pyrrolo[2,3-b]pyridine: A new scaffold for human neutrophil elastase (HNE) inhibitors; Bioorganic & Medicinal Chemistry; Vol. 26, Iss. 21
| Parent link: | Bioorganic & Medicinal Chemistry Vol. 26, Iss. 21.— 2018.— [P. 5583-5595] |
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| Institution som forfatter: | |
| Andre forfattere: | , , , , , , , , , |
| Summary: | Title screen Human neutrophil elastase (HNE) is a potent serine protease belonging to the chymotrypsin family. It is an important target for the development of novel and selective inhibitors for the treatment of inflammatory diseases, especially pulmonary pathologies. Here, we report the synthesis and biological evaluation of a new series of HNE inhibitors with a pyrrolo[2,3-b]pyridine scaffold, which is an isomer of our previously reported indazoles, in order to assess how a shift of the nitrogen from position 2 to position 7 influences activity. The majority of new compounds were effective HNE inhibitors and had IC50 values in the micromolar/submicromolar range, with some compounds active in low nanomolar levels. For example, 2a and 2b inhibited HNE with IC50 values of 15 and 14?nM, respectively. Molecular modeling of compounds differing in the position of heteroatom(s) in the bicyclic moiety and in the oxadiazole ring demonstrated that the calculated geometries of enzyme-inhibitor complexes were in agreement with the observed biological activities. Docking experiments showed that orientation of the active pyrrolo[2,3-b]pyridines in the HNE catalytic triad Ser195-His57-Asp102 correlated with effectiveness of the inhibitor interaction with the enzyme. Thus, the pyrrolo[2,3-b]pyridine scaffold represents a novel scaffold for the development of potent HNE inhibitors. Режим доступа: по договору с организацией-держателем ресурса |
| Sprog: | engelsk |
| Udgivet: |
2018
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| Fag: | |
| Online adgang: | https://doi.org/10.1016/j.bmc.2018.09.034 |
| Format: | Electronisk Book Chapter |
| KOHA link: | https://koha.lib.tpu.ru/cgi-bin/koha/opac-detail.pl?biblionumber=659744 |
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| 200 | 1 | |a 1H-pyrrolo[2,3-b]pyridine: A new scaffold for human neutrophil elastase (HNE) inhibitors |f L. Crocetti, M. P. Giovannoni, I. A. Shchepyotkin [et al.] | |
| 203 | |a Text |c electronic | ||
| 300 | |a Title screen | ||
| 320 | |a [References: 38 tit.] | ||
| 330 | |a Human neutrophil elastase (HNE) is a potent serine protease belonging to the chymotrypsin family. It is an important target for the development of novel and selective inhibitors for the treatment of inflammatory diseases, especially pulmonary pathologies. Here, we report the synthesis and biological evaluation of a new series of HNE inhibitors with a pyrrolo[2,3-b]pyridine scaffold, which is an isomer of our previously reported indazoles, in order to assess how a shift of the nitrogen from position 2 to position 7 influences activity. The majority of new compounds were effective HNE inhibitors and had IC50 values in the micromolar/submicromolar range, with some compounds active in low nanomolar levels. For example, 2a and 2b inhibited HNE with IC50 values of 15 and 14?nM, respectively. Molecular modeling of compounds differing in the position of heteroatom(s) in the bicyclic moiety and in the oxadiazole ring demonstrated that the calculated geometries of enzyme-inhibitor complexes were in agreement with the observed biological activities. Docking experiments showed that orientation of the active pyrrolo[2,3-b]pyridines in the HNE catalytic triad Ser195-His57-Asp102 correlated with effectiveness of the inhibitor interaction with the enzyme. Thus, the pyrrolo[2,3-b]pyridine scaffold represents a novel scaffold for the development of potent HNE inhibitors. | ||
| 333 | |a Режим доступа: по договору с организацией-держателем ресурса | ||
| 461 | |t Bioorganic & Medicinal Chemistry | ||
| 463 | |t Vol. 26, Iss. 21 |v [P. 5583-5595] |d 2018 | ||
| 610 | 1 | |a электронный ресурс | |
| 610 | 1 | |a труды учёных ТПУ | |
| 610 | 1 | |a human neutrophil elastase | |
| 610 | 1 | |a inhibitor | |
| 610 | 1 | |a pyrrolo[2,3-b]pyridine | |
| 610 | 1 | |a molecular docking | |
| 610 | 1 | |a нейтрофильная фаза | |
| 610 | 1 | |a ингибиторы | |
| 610 | 1 | |a пирролы | |
| 610 | 1 | |a пиридин | |
| 610 | 1 | |a пиридины | |
| 610 | 1 | |a молекулярная стыковка | |
| 701 | 1 | |a Crocetti |b L. |g Letizia | |
| 701 | 1 | |a Giovannoni |b M. P. |g Maria Paola | |
| 701 | 1 | |a Shchepyotkin |b I. A. |c doctor-biophysicist |c leading researcher of Tomsk Polytechnic University, candidate of medical science |f 1962- |g Igor Aleksandrovich |3 (RuTPU)RU\TPU\pers\37358 | |
| 701 | 1 | |a Quinn |b M. |g Mark | |
| 701 | 1 | |a Khlebnikov |b A. I. |c Chemist |c Professor of Tomsk Polytechnic University |f 1963- |g Andrey Ivanovich |3 (RuTPU)RU\TPU\pers\33927 |9 17500 | |
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