| 000 | 03668nlm1a2200529 4500 | ||
|---|---|---|---|
| 001 | 663930 | ||
| 005 | 20231030041912.0 | ||
| 035 | _a(RuTPU)RU\TPU\network\35100 | ||
| 035 | _aRU\TPU\network\28532 | ||
| 090 | _a663930 | ||
| 100 | _a20210318a2021 k y0engy50 ba | ||
| 101 | 0 | _aeng | |
| 102 | _aNL | ||
| 135 | _adrcn ---uucaa | ||
| 181 | 0 | _ai | |
| 182 | 0 | _ab | |
| 200 | 1 |
_aExploration of nitrogen heterocycle scaffolds for the development of potent human neutrophil elastase inhibitors _fN. Cantini, A. I. Khlebnikov, L. Crocetti [et al.] |
|
| 203 |
_aText _celectronic |
||
| 300 | _aTitle screen | ||
| 320 | _a[References: 59 tit.] | ||
| 330 | _aHuman 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 | _aРежим доступа: по договору с организацией-держателем ресурса | ||
| 461 | _tBioorganic & Medicinal Chemistry | ||
| 463 |
_tVol. 29, iss. 1 _v[115836, 17 p.] _d2021 |
||
| 610 | 1 | _aэлектронный ресурс | |
| 610 | 1 | _aтруды учёных ТПУ | |
| 610 | 1 | _ahuman neutrophil elastaseInhibitors | |
| 610 | 1 | _anitrogen heterocycle | |
| 610 | 1 | _astability | |
| 610 | 1 | _aADMET | |
| 610 | 1 | _amolecular docking | |
| 610 | 1 | _aингибиторы | |
| 610 | 1 | _aмолекулярная стыковка | |
| 701 | 1 |
_aCantini _bN. _gNiccolo |
|
| 701 | 1 |
_aKhlebnikov _bA. I. _cChemist _cProfessor of Tomsk Polytechnic University _f1963- _gAndrey Ivanovich _2stltpush _3(RuTPU)RU\TPU\pers\33927 |
|
| 701 | 1 |
_aCrocetti _bL. _gLetizia |
|
| 701 | 1 |
_aShchepyotkin _bI. A. _cdoctor-biophysicist _cleading researcher of Tomsk Polytechnic University, candidate of medical science _f1962- _gIgor Aleksandrovich _2stltpush _3(RuTPU)RU\TPU\pers\37358 |
|
| 701 | 1 |
_aFloresta _bG. _gGiuseppe |
|
| 701 | 1 |
_aGuerrini _bG. _gGabriella |
|
| 701 | 1 |
_aVergelli _bC. _gClaudia |
|
| 701 | 1 |
_aBartolucci _bG. _gGianluca |
|
| 701 | 1 |
_aQuinn _bM. _gMark |
|
| 701 | 1 |
_aGiovannoni _bM. P. _gMaria Paola |
|
| 712 | 0 | 2 |
_aНациональный исследовательский Томский политехнический университет _bИнженерная школа новых производственных технологий _bНаучно-образовательный центр Н. М. Кижнера _h7872 _2stltpush _3(RuTPU)RU\TPU\col\23556 |
| 801 | 2 |
_aRU _b63413507 _c20210318 _gRCR |
|
| 856 | 4 | _uhttps://doi.org/10.1016/j.bmc.2020.115836 | |
| 942 | _cCF | ||