6752-16-5Relevant articles and documents
Exploration of nitrogen heterocycle scaffolds for the development of potent human neutrophil elastase inhibitors
Cantini, Niccolò,Khlebnikov, Andrei I.,Crocetti, Letizia,Schepetkin, Igor A.,Floresta, Giuseppe,Guerrini, Gabriella,Vergelli, Claudia,Bartolucci, Gianluca,Quinn, Mark T.,Giovannoni, Maria Paola
, (2020/11/25)
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.
Pharmacophore modeling, 3D-QSAR, synthesis, and anti-lung cancer evaluation of novel thieno[2,3-d][1,2,3]triazines targeting EGFR
Abdel Aziz, Yasmine M.,Elewa, Marwa,Elgawish, Mohamed S.,Elrayess, Ranza,Elshihawy, Hosam A.,Said, Mohamed M.
, (2020/01/24)
Two series of thieno[2,3-d][1,2,3]triazine derivatives were designed, synthesized, and biologically evaluated as potential epidermal growth factor receptor (EGFR) inhibitors targeting the non-small-cell lung cancer cell line H1299. Most of the synthesized compounds displayed IC50 values ranging from 25 to 58 nM against H1299, which are superior to that of gefitinib (40 μM). 3-(5,6,7,8-Tetrahydro-7H-cyclohexa[4:5]thieno[2,3-d]-1,2,3-triazin-4-ylamino)benzene-1,3-diamine (6b) achieved the highest cytotoxic activity against H1299 with an IC50 value of 25 nM; it had the ability to decrease the EGFR concentration in H1299 cells from 7.22 to 2.67 pg/ml. In vitro, the IC50 value of compound 6b was 0.33 nM against EGFR, which is superior to that of gefitinib at 1.9 nM and erlotinib at 4 nM. The three-dimensional quantitative structure–activity relationships and molecular modeling studies revealed comparable binding modes of compound 6b, gefitinib, and erlotinib in the EGFR active site. The in silico ADME (absorption, distribution, metabolism, and excretion) prediction parameters of this compound revealed promising pharmacokinetic and physicochemical properties. Moreover, DFT (density functional theory) calculations showed the high reactivity of compound 6b toward the EGFR compared with other compounds. The designed compound 6b might serve as an encouraging lead compound for the discovery of promising anti-lung cancer agents targeting EGFR.
A multifunctional therapeutic approach: Synthesis, biological evaluation, crystal structure and molecular docking of diversified 1H-pyrazolo[3,4-b]pyridine derivatives against Alzheimer's disease
Umar, Tarana,Shalini, Shruti,Raza, Md Kausar,Gusain, Siddharth,Kumar, Jitendra,Seth, Prerna,Tiwari, Manisha,Hoda, Nasimul
, p. 2 - 19 (2019/05/06)
2-(piperazin-1-yl)–N-(1H-pyrazolo[3,4-b]pyridin-3-yl)acetamides are described as a new class of selective and potent acetylcholinesterase (AChE) inhibitors and amyloid β aggregation inhibitors. Formation of synthesized compounds (P1–P9) was justified via H1 NMR, C13 NMR, mass spectra and single crystal X-Ray diffraction study. All compounds were evaluated for their acetylcholinesterase and butyrylcholinesterase inhibitory activity, inhibition of self-mediated Aβ aggregation and Cu(II)-mediated Aβ aggregation. Also, docking study carried out was in concordance with in vitro results. The most potent molecule amongst the derivatives exhibited excellent anti-AChE activity (IC50 = 4.8 nM). Kinetic study of P3 suggested it to be a mixed type inhibitor. In vitro study revealed that all the compounds are capable of inhibiting self-induced β-amyloid (Aβ) aggregation with the highest inhibition percentage to be 81.65%. Potency of P1 and P3 to inhibit self-induced Aβ1-42 aggregation was ascertained by TEM analysis. Compounds were also evaluated for their Aβ disaggregation, antioxidation, metal-chelation activity.
4-Amino-7,8-dihydro-1,6-naphthyridin-5(6 H)-ones as Inhaled Phosphodiesterase Type 4 (PDE4) Inhibitors: Structural Biology and Structure-Activity Relationships
Roberts, Richard S.,Sevilla, Sara,Ferrer, Manel,Taltavull, Joan,Hernández, Bego?a,Segarra, Victor,Gràcia, Jordi,Lehner, Martin D.,Gavaldà, Amadeu,Andrés, Miriam,Cabedo, Judit,Vilella, Dolors,Eichhorn, Peter,Calama, Elena,Carcasona, Carla,Miralpeix, Montserrat
, p. 2472 - 2489 (2018/03/26)
Rational design of a novel template of naphthyridinones rapidly led to PDE4 inhibitors with subnanomolar enzymatic potencies. X-ray crystallography confirmed the binding mode of this novel template. We achieved compounds with double-digit picomolar enzymatic potencies through further structure-based design by targeting both the PDE4 enzyme metal-binding pocket and occupying the solvent-filled pocket. A strategy for lung retention and long duration of action based on low aqueous solubility was followed. In vivo efficacies were measured in a rat lung neutrophilia model by suspension microspray and dry powder administration. Suspension microspray of potent compounds showed in vivo efficacy with a clear dose-response. Despite sustained lung levels, dry powder administration performed much less well and without proper dose-response, highlighting clear differences between the two formulations. This indicates a deficiency in the low aqueous solubility strategy for long duration lung efficacy.
Use of 3-(trifluoromethyl)-1H-pyrazolo-[3,4-b]pyridine as a versatile building block
Schirok, Hartmut,Griebenow, Nils,Fürstner, Chantal,Dilmac, Alicia M.
, p. 5597 - 5601 (2015/08/03)
A one-pot multigram synthesis of 3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine starting from 2-fluoropyridine using directed ortho metallation (DoM) technique is described. The compound contains an anionically activatable trifluoromethyl group and is a versatile building block for the microwave assisted synthesis of 3-substituted 1H-pyrazolo[3,4-b]pyridines.
Copper-catalyzed sequential N-arylation of C-amino-NH-azoles
Nageswar Rao,Rasheed, Sk.,Vishwakarma, Ram A.,Das, Parthasarathi
supporting information, p. 12911 - 12914 (2014/12/11)
Copper(ii)-catalyzed boronic acid promoted C-N bond cross-coupling reactions have been successfully developed for sequential N-arylation of C-amino-NH-azoles. These general protocols are compatible with a variety of aryl/hetero-aryl boronic acids and provided rapid access to a diverse array of diarylaminoazole derivatives in a two-step sequence or in one-pot. This journal is
Design, synthesis and evaluation of 7-azaindazolyl-indolyl-maleimides as glycogen synthase kinase-3β (GSK-3β) inhibitors
Ye, Qing,Shen, Yanhong,Zhou, Yubo,Lv, Dan,Gao, Jianrong,Li, Jia,Hu, Yongzhou
, p. 361 - 371 (2013/10/01)
A series of 7-azaindazolyl-indolyl-maleimides were designed, synthesized and evaluated for their GSK-3β inhibitory activity. Most compounds exhibited potent activity against GSK-3β. Among them, compounds 17a, 17b, 17g, 17i, 29a and 30 significantly reduced Aβ-induced Tau hyperphosphorylation, showin;g the inhibition of GSK-3β at the cell level. Preliminary structure-activity relationships were discussed based on the experimental data obtained.
Compounds as syk kinase inhibitors
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Paragraph 0126; 0127, (2013/03/26)
The present invention relates to a compound of formula (I), to the process for preparing such compounds and to their use in the treatment of a pathological condition or disease susceptible to amelioration by inhibition of Syk kinase.
Synthesis and structure of 3,4-dihydropyrido[2',3':3,4]pyrazolo[1,5-a][1,3, 5]triazin-2-amines [1]
Dolzhenko, Anton V.,Bai, Shiqi,Dolzhenko, Anna V.,Chui, Wai Keung
, p. 763 - 767 (2012/10/29)
A new convenient synthon for heterocyclic chemistry, namely 1H-pyrazolo[3,4-b]pyridin-3-ylguanidine was successfully prepared by selective guanylation of 1H-pyrazolo[3,4-b]pyridin-3-amine. A series of 3,4-dihydropyrido[2',3':3,4]pyrazolo[1,5-a][1,3,5]triazin-2-amines was synthesized from 1H-pyrazolo[3,4-b]pyridin-3-ylguanidine using aldehydes or ketones as one-carbon inserting reagents. The tautomeric preferences of the products were determined using spectroscopic (e.g., 2D NOESY NMR) and single crystal X-ray diffraction data.
New 7,8-dihydro-1,6-naphthyridin-5(6h)-one-derivatives as PDE4 inhibitors
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Page/Page column 36, (2011/11/07)
New 7,8-dihydro-1,6-naphthyridin-5(6H)-one derivatives derivatives having the chemical structure of formula (I) are disclosed; as well as process for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of the phosphodiesterase IV (PDE4).
