共查询到20条相似文献,搜索用时 9 毫秒
1.
《Bioorganic & medicinal chemistry letters》2014,24(12):2635-2639
The discovery and optimization of a series of tetrahydropyridopyrimidine based extracellular signal-regulated kinase (Erks) inhibitors discovered via HTS and structure based drug design is reported. The compounds demonstrate potent and selective inhibition of Erk2 and knockdown of phospho-RSK levels in HepG2 cells and tumor xenografts. 相似文献
2.
Jackson RW LaPorte MG Herbertz T Draper TL Gaboury JA Rippin SR Patel R Chunduru SK Benetatos CA Young DC Burns CJ Condon SM 《Bioorganic & medicinal chemistry letters》2011,21(11):3227-3231
We describe the structure-activity relationship of the C7-position of pyrano[3,4-b]indole-based inhibitors of HCV NS5B polymerase. Further exploration of the allosteric binding site led to the discovery of the significantly more potent compounds 13 and 14. 相似文献
3.
Arnould JC Delouvrié B Boutron P Dossetter AG Foote KM Hamon A Hancox U Harris CS Hutton M Lamorlette M Matusiak Z 《Bioorganic & medicinal chemistry letters》2007,17(23):6448-6454
A new class of small-molecule GnRH antagonists, the thieno[2,3-b]pyrroles, was designed. Herein, the synthesis and structure-activity relationships are described. Substitution at the C4 position was investigated; during this study, it was observed that introducing piperazines and piperidines improved the physical properties of the compounds while retaining good in vitro potency. This exploration led to the discovery of amidopiperidines with improved pharmacokinetic properties. 相似文献
4.
Lin R Connolly PJ Lu Y Chiu G Li S Yu Y Huang S Li X Emanuel SL Middleton SA Gruninger RH Adams M Fuentes-Pesquera AR Greenberger LM 《Bioorganic & medicinal chemistry letters》2007,17(15):4297-4302
A series of 3,5-disubstituted pyrazolo[3,4-b]pyridine cyclin-dependent kinase (CDK) inhibitors was synthesized. These compounds showed potent and selective CDK inhibitory activities and inhibited in vitro cellular proliferation in cultured human tumor cells. Selected compounds were evaluated in an in vivo tumor xenograft model. The synthesis and biological evaluation of these pyrazolo[3,4-b]pyridines and related compounds are reported. 相似文献
5.
Mourad Chioua Abdelouahid Samadi Elena Soriano Olivier Lozach Laurent Meijer José Marco-Contelles 《Bioorganic & medicinal chemistry letters》2009,19(16):4566-4569
The synthesis and biological evaluation of a number of differently substituted 3,6-diamino-1H-pyrazolo[3,4-b]pyridine derivatives are reported. From the inhibition results on a selection of disease-relevant protein kinases [IC50 (μM) DYRK1A = 11; CDK5 = 0.41; GSK-3 = 1.5] we have observed that 3,6-diamino-4-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (4) constitutes a potential new and simple lead compound in the search of drugs for the treatment of Alzheimer’s disease. 相似文献
6.
Bharate SB Mahajan TR Gole YR Nambiar M Matan TT Kulkarni-Almeida A Balachandran S Junjappa H Balakrishnan A Vishwakarma RA 《Bioorganic & medicinal chemistry》2008,16(15):7167-7176
In the present article, we have synthesized three different series of pyrazolo[3,4-b]pyridines and their structural analogues using novel synthetic strategy involving one-pot condensation of 5,6-dihydro-4H-pyran-3-carbaldehyde/2-formyl-3,4,6-tri-O-methyl-D-glucal/chromone-3-carbaldehyde with heteroaromatic amines. All synthesized compounds were evaluated for their anti-inflammatory activity against TNF-alpha and IL-6. Out of 28 compounds screened, 40, 51, 52 and 56 exhibited promising activity against IL-6 with 60-65% inhibition at 10 microM concentration. Amongst these, 51, 52 and 56 showed potent IL-6 inhibitory activity with IC(50)'s of 0.2, 0.3 and 0.16 microM, respectively. Compound 56 was not cytotoxic in CCK-8 cells up to the concentration of >100 microM. 相似文献
7.
Misra RN Rawlins DB Xiao HY Shan W Bursuker I Kellar KA Mulheron JG Sack JS Tokarski JS Kimball SD Webster KR 《Bioorganic & medicinal chemistry letters》2003,13(6):1133-1136
1H-Pyrazolo[3,4-b]pyridine 3 (SQ-67563) has been shown to be a potent, selective inhibitor of CDK1/CDK2 in vitro. In cells 3 acts as a cytotoxic agent with the ability to block cell cycle progression and/or induce apoptosis. The solid state structure of 3 bound to CDK2 shows 3 resides coincident with the ATP purine binding site and forms important H-bonding interactions with Leu83 on the protein backbone. 相似文献
8.
Yakaiah T Lingaiah BP Narsaiah B Shireesha B Ashok Kumar B Gururaj S Parthasarathy T Sridhar B 《Bioorganic & medicinal chemistry letters》2007,17(12):3445-3453
A series of novel pyrimido[1,2-b]indazoles 5, 7 have been prepared from 3-trifluoromethyl-5-phenyl-2,6-dicyano anilines 1 via novel indazole regioisomers 3 and 4 through a facile strategy. Specific examples were evaluated for anticancer activity in vitro and found to exhibit promising activity against A-549 cell lines and are more effective than Etoposide. QSAR models were developed and validated by cross-validation method. The results of the best QSAR model were further compared with the crystal structure of tubulin protein. The binding energies estimated were found to have a good correlation with the experimental inhibitory potencies. 相似文献
9.
Synthesis and structure-activity relationships of 1-phenylpyrazoles as xanthine oxidase inhibitors 总被引:1,自引:0,他引:1
Ishibuchi S Morimoto H Oe T Ikebe T Inoue H Fukunari A Kamezawa M Yamada I Naka Y 《Bioorganic & medicinal chemistry letters》2001,11(7):879-882
A series of 1-phenylpyrazoles was evaluated for inhibitory activity against xanthine oxidase in vitro. Of the compounds prepared, 1-(3-cyano-4-neopentyloxyphenyl)pyrazole-4-carboxylic acid (Y-700) had the most potent enzyme inhibition and displayed longer-lasting hypouricemic action than did allopurinol in a rat model of hyperuricemia induced by the uricase inhibitor potassium oxonate. 相似文献
10.
Five novel 1H-pyrrolo[2,3-b]pyridine or 1H-pyrazolo[3,4-b]pyridine derivatives, with a methylene, sulfur, sulfoxide or cyclopropyl group as a linker, were designed, synthesized and biologically evaluated against c-Met and ALK. The development of these methods of compound synthesis may provide an important reference for the construction of novel 7-azaindole and 7-azaindazole derivatives with a single atom linker. The enzyme assay and cell assay in vitro showed that compound 9 displayed strong c-Met kinase inhibition with IC50 of 22.8 nM, moderate ALK kinase inhibition, and strong cell inhibition with MKN-45 IC50 of 329 nM and EBC-1 IC50 of 479 nM. In order to find the better candidate compounds, compounds 8, 9 and 10 have been selected as tool compounds for further optimization. 相似文献
11.
Peptide hydroxamic acids as inhibitors of thermolysin 总被引:4,自引:0,他引:4
12.
Jianyou Shi Guobin Xu Wei Zhu Haoyu Ye Shengyong Yang Youfu Luo Jing Han Jincheng Yang Rui Li Yuquan Wei Lijuan Chen 《Bioorganic & medicinal chemistry letters》2010,20(14):4273-4278
Two series of 3-aminopyrazole compounds including 24 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazoles and 16 pyrazolo[3,4-b]pyridines were synthesized and evaluated against HCT116, A549, and A2780 tumor cell lines. Among them, three compounds were found to have the ideal anti-proliferative activities in vitro. Docking experiments showed that the novel pyrazolo[3,4-b]pyridines share the similar interaction mode with Aurora-A kinase as PHA739358. 相似文献
13.
David B. Belanger Patrick J. Curran Alan Hruza Johannes Voigt Zhaoyang Meng Amit K. Mandal M. Arshad Siddiqui Andrea D. Basso Kimberly Gray 《Bioorganic & medicinal chemistry letters》2010,20(17):5170-5174
The synthesis and structure–activity relationships (SAR) of novel, potent imidazo[1,2-a]pyrazine-based Aurora kinase inhibitors are described. The X-ray crystal structure of imidazo[1,2-a]pyrazine Aurora inhibitor 1j is disclosed. Compound 10i was identified as lead compound with a promising overall profile. 相似文献
14.
Bassem H. Naguib 《Journal of enzyme inhibition and medicinal chemistry》2016,31(6):1718-1725
Three series of 5-bromo-thieno[2,3-b]pyridines bearing amide or benzoyl groups at position 2 were prepared as pim-1 inhibitors. All the prepared compounds were tested for their pim-1 enzyme inhibitory activity. Two compounds (3c and 5b) showed moderate pim-1 inhibitory activity with IC50 of 35.7 and 12.71?μM, respectively. Three other compounds (3d, 3g and 6d) showed poor pim-1 inhibition. The most active compounds were tested for their cytotoxic activity on five cell lines [MCF7, HEPG2, HCT116, A549 and PC3]. Compound 3g was the most potent cytotoxic agent on almost all the cell lines tested. 相似文献
15.
Chen J Deady LW Desneves J Kaye AJ Finlay GJ Baguley BC Denny WA 《Bioorganic & medicinal chemistry》2000,8(10):2461-2466
New substituted indeno[1,2-b]quinoline-6-carboxamides, [1]benzothieno[3,2-b]quinoline-4-carboxamides and 10H-quindoline-4-carboxamides were prepared from methyl 2-amino-3-formylbenzoate by a new Friedlander synthesis. Evaluation of these carboxamides for cytotoxicity in a panel of cell lines showed that small lipophilic substituents in the non-carboxamide ring, in a pseudo-peri position to the side chain, significantly increased cytotoxic potency while retaining a pattern of cytotoxicity consistent with a non-topo II mode of action. The methyl-substituted indeno[1,2-b]quinoline-6-carboxamide demonstrated substantial effectiveness (20-day growth delays) in a sub-cutaneous colon 38 in vivo tumor model. This is comparable to that reported for the dual topo I/II inhibitor DACA that is in clinical trial. 相似文献
16.
Liu M Xin Z Clampit JE Wang S Gum RJ Haasch DL Trevillyan JM Abad-Zapatero C Fry EH Sham HL Liu G 《Bioorganic & medicinal chemistry letters》2006,16(10):2590-2594
A novel class of 1,9-dihydro-9-hydroxypyrazolo[3,4-b]quinolin-4-ones as c-Jun-N-terminal kinase (JNK) inhibitors is described. These compounds were synthesized via the condensation of 2-nitrobenzaldehydes and hydroxypyrazoles. The structure-activity relationships (SAR) and kinase selectivity profile of the inhibitors are also discussed. Compound 16 was identified as a potent JNK inhibitor with good cellular potency. 相似文献
17.
Ortega MA Montoya ME Zarranz B Jaso A Aldana I Leclerc S Meijer L Monge A 《Bioorganic & medicinal chemistry》2002,10(7):2177-2184
Protein kinases are involved in most physiological processes and in numerous diseases. Therefore, inhibitors of protein kinases have therefore a wide therapeutic potential. While screening for inhibitors of cyclin-dependent kinases (CDK's) and glycogen synthase kinase-3 (GSK-3), we identified pyrazolo[3,4-b]quinoxalines as sub-micromolar inhibitors of CDK1/cyclin B. A preliminary structure-activity relationship study suggests that this family of compounds can be optimized to inhibit CDK's and GSK-3. Compounds were tested for their anti-proliferative activity and the results show that several of them displayed a significant inhibitory effect on CDK1/cyclin B. The most active compound (1) was also tested against the brain kinases CDK5/p25 and GSK-3, and proved to be a good inhibitor of both of them. On the contrary, none of the compounds showed any activity in the CDC25 phosphatase assay. As an additional approach, affinity chromatography on immobilized pyrazolo[3,4-b]quinoxalines will be used to identify the intracellular targets of this family of compounds. 相似文献
18.
Chern JH Shia KS Hsu TA Tai CL Lee CC Lee YC Chang CS Tseng SN Shih SR 《Bioorganic & medicinal chemistry letters》2004,14(10):2519-2525
A series of pyrazolo[3,4-d]pyrimidines were synthesized and their antiviral activity was evaluated in a plaque reduction assay. It is very interesting that this class of compounds provide remarkable evidence that they are very specific for human enteroviruses, in particular, coxsackieviruses. Some derivatives proved to be highly effective in inhibiting enterovirus replication at nanomolar concentrations. SAR studies revealed that the phenyl group at the N-1 position and the hydrophobic diarylmethyl group at the piperazine largely influenced the in vitro antienteroviral activity of this new class of potent antiviral agents. It was found that the pyrazolo[3,4-d]pyrimidines with a thiophene substituent, such as compounds 20-24, in general exhibited high activity against coxsackievirus B3 (IC(50) = 0.063-0.089 microM) and moderate activity against enterovirus 71 (IC(50) = 0.32-0.65 microM) with no apparent cytotoxic effect toward RD (rhabdomyosarcoma) cell lines (CC(50) > 25 microM). 相似文献
19.
Pevet I Brulé C Tizot A Gohier A Cruzalegui F Boutin JA Goldstein S 《Bioorganic & medicinal chemistry》2011,19(8):2517-2528
Among the recently investigated targets for cancer therapy is the c-Src non-receptor tyrosine kinase. Indeed research around deregulated activity of this enzyme has proven its role in tumor progression, while the beneficial effects of c-Src inhibitors in several pathological models has also been demonstrated. We report here the preparation and pharmacological profile of a novel series of c-Src inhibitors that was elaborated around a 3-amino-thieno[2,3-b]pyridine discovered during an HTS campaign. c-Src enzyme inhibition and c-Src inhibition were investigated in a series of related compounds derived from the initial hit. Molecular modeling as well as X-ray studies on one active compound allowed us to hypothesize on ligand orientation and interactions within the ATP hydrophobic pocket. Design and synthesis of structural analogs then led to new ligands possessing quite efficient enzymatic and c-Src inhibition. The structure-activity elements disclosed in this study shed light on the role played by substituents on the thienopyridine ring as well as the impact of other aromatic moieties in the molecule when interacting with the enzyme. 相似文献
20.
Leal B Afonso IF Rodrigues CR Abreu PA Garrett R Pinheiro LC Azevedo AR Borges JC Vegi PF Santos CC da Silveira FC Cabral LM Frugulhetti IC Bernardino AM Santos DO Castro HC 《Bioorganic & medicinal chemistry》2008,16(17):8196-8204
Antibacterial resistance is a complex problem that contributes to health and economic losses worldwide. The Staphylococcus epidermidis is an important nosocomial pathogen that affects immunocompromised patients or those with indwelling devices. Currently, there are several resistant strains including S. epidermidis that became an important medical issue mainly in hospital environment. In this work, we report the biological and theoretical evaluations of a 4-(arylamino)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acids series (1, 1a-m) and the comparison with a new isosteric ring nucleus series, 4-(arylamino)thieno[2,3-b]pyridine-5-carboxylic acids derivatives (2, 2a-m). Our results revealed the 1H-pyrazolo[3,4-b]pyridine derivatives significant antibacterial activity against a drug-resistant S. epidermidis clinical strain in contrast to the thieno[2,3-b]pyridine series. The minimal inhibitory concentration (MIC) of the most active derivatives (1a, 1c, 1e, and 1f) against S. epidermidis was similar to that of oxacillin and twofold better than chloramphenicol. Interestingly, the position of the functional groups has a great impact on the activity as observed in our structure-activity relationship (SAR) study. The SAR of 1H-pyrazolo[3,4-b]pyridine derivatives shows that the highest inhibitory activity is observed when the meta position is occupied by electronegative substituents. The molecular modeling analysis of frontier molecular orbitals revealed that the LUMO density is less intense in meta than in ortho and para positions for both series (1 and 2), whereas HOMO density is overconcentrated in 1H-pyrazolo[3,4-b]pyridine ring nucleus compared to the thieno[2,3-b]pyridine system. The most active derivatives of series 1 were submitted to in silico ADMET screening, which confirmed these compounds as potential antibacterial candidates. 相似文献