Exploration of nitrogen heterocycle scaffolds for the development of potent human neutrophil elastase inhibitors; Bioorganic & Medicinal Chemistry; Vol. 29, iss. 1
| Parent link: | Bioorganic & Medicinal Chemistry Vol. 29, iss. 1.— 2021.— [115836, 17 p.] |
|---|---|
| Corporate Author: | |
| Other Authors: | , , , , , , , , , |
| Summary: | Title screen Human neutrophil elastase (HNE) is a potent protease that plays an important physiological role in many processes but is also involved in a variety of pathologies that affect the pulmonary system. Thus, compounds able to inhibit HNE proteolytic activity could represent effective therapeutics. We present here a new series of pyrazolopyridine and pyrrolopyridine derivatives as HNE inhibitors designed as modifications of our previously synthesized indazoles and indoles in order to evaluate effects of the change in position of the nitrogen and/or the insertion of an additional nitrogen in the scaffolds on biological activity and chemical stability. We obtained potent HNE inhibitors with IC50 values in the low nanomolar range (10–50 nM), and some compounds exhibited improved chemical stability in phosphate buffer (t1/2 > 6 h). Molecular modeling studies demonstrated that inhibitory activity was strictly dependent on the formation of a Michaelis complex between the OH group of HNE Ser195 and the carbonyl carbon of the inhibitor. Moreover, in silico ADMET calculations predicted that most of the new compounds would be optimally absorbed, distributed, metabolized, and excreted. Thus, these new and potent HNE inhibitors represent novel leads for future therapeutic development. Режим доступа: по договору с организацией-держателем ресурса |
| Language: | English |
| Published: |
2021
|
| Subjects: | |
| Online Access: | https://doi.org/10.1016/j.bmc.2020.115836 |
| Format: | MixedMaterials Electronic Book Chapter |
| KOHA link: | https://koha.lib.tpu.ru/cgi-bin/koha/opac-detail.pl?biblionumber=663930 |
MARC
| LEADER | 00000naa0a2200000 4500 | ||
|---|---|---|---|
| 001 | 663930 | ||
| 005 | 20250429161114.0 | ||
| 035 | |a (RuTPU)RU\TPU\network\35100 | ||
| 035 | |a RU\TPU\network\28532 | ||
| 090 | |a 663930 | ||
| 100 | |a 20210318d2021 k||y0rusy50 ba | ||
| 101 | 0 | |a eng | |
| 102 | |a NL | ||
| 135 | |a drcn ---uucaa | ||
| 181 | 0 | |a i | |
| 182 | 0 | |a b | |
| 200 | 1 | |a Exploration of nitrogen heterocycle scaffolds for the development of potent human neutrophil elastase inhibitors |f N. Cantini, A. I. Khlebnikov, L. Crocetti [et al.] | |
| 203 | |a Text |c electronic | ||
| 300 | |a Title screen | ||
| 320 | |a [References: 59 tit.] | ||
| 330 | |a Human neutrophil elastase (HNE) is a potent protease that plays an important physiological role in many processes but is also involved in a variety of pathologies that affect the pulmonary system. Thus, compounds able to inhibit HNE proteolytic activity could represent effective therapeutics. We present here a new series of pyrazolopyridine and pyrrolopyridine derivatives as HNE inhibitors designed as modifications of our previously synthesized indazoles and indoles in order to evaluate effects of the change in position of the nitrogen and/or the insertion of an additional nitrogen in the scaffolds on biological activity and chemical stability. We obtained potent HNE inhibitors with IC50 values in the low nanomolar range (10–50 nM), and some compounds exhibited improved chemical stability in phosphate buffer (t1/2 > 6 h). Molecular modeling studies demonstrated that inhibitory activity was strictly dependent on the formation of a Michaelis complex between the OH group of HNE Ser195 and the carbonyl carbon of the inhibitor. Moreover, in silico ADMET calculations predicted that most of the new compounds would be optimally absorbed, distributed, metabolized, and excreted. Thus, these new and potent HNE inhibitors represent novel leads for future therapeutic development. | ||
| 333 | |a Режим доступа: по договору с организацией-держателем ресурса | ||
| 461 | |t Bioorganic & Medicinal Chemistry | ||
| 463 | |t Vol. 29, iss. 1 |v [115836, 17 p.] |d 2021 | ||
| 610 | 1 | |a электронный ресурс | |
| 610 | 1 | |a труды учёных ТПУ | |
| 610 | 1 | |a human neutrophil elastaseInhibitors | |
| 610 | 1 | |a nitrogen heterocycle | |
| 610 | 1 | |a stability | |
| 610 | 1 | |a ADMET | |
| 610 | 1 | |a molecular docking | |
| 610 | 1 | |a ингибиторы | |
| 610 | 1 | |a молекулярная стыковка | |
| 701 | 1 | |a Cantini |b N. |g Niccolo | |
| 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 | |
| 701 | 1 | |a Crocetti |b L. |g Letizia | |
| 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 Floresta |b G. |g Giuseppe | |
| 701 | 1 | |a Guerrini |b G. |g Gabriella | |
| 701 | 1 | |a Vergelli |b C. |g Claudia | |
| 701 | 1 | |a Bartolucci |b G. |g Gianluca | |
| 701 | 1 | |a Quinn |b M. |g Mark | |
| 701 | 1 | |a Giovannoni |b M. P. |g Maria Paola | |
| 712 | 0 | 2 | |a Национальный исследовательский Томский политехнический университет |b Инженерная школа новых производственных технологий |b Научно-образовательный центр Н. М. Кижнера |3 (RuTPU)RU\TPU\col\23556 |
| 801 | 0 | |a RU |b 63413507 |c 20210318 |g RCR | |
| 850 | |a 63413507 | ||
| 856 | 4 | |u https://doi.org/10.1016/j.bmc.2020.115836 | |
| 942 | |c CF | ||