共查询到20条相似文献,搜索用时 31 毫秒
1.
Swahn BM Xue Y Arzel E Kallin E Magnus A Plobeck N Viklund J 《Bioorganic & medicinal chemistry letters》2006,16(5):1397-1401
The design and synthesis of a new series of c-Jun N-terminal kinase-3 (JNK3) inhibitors with selectivity against JNK1 are reported. The novel series of substituted 2'-anilino-4,4'-bipyridines were designed based on a combination of hits from high throughput screening and X-ray crystal structure information of compounds crystallized into the JNK3 ATP binding active site. 相似文献
2.
Angell RM Atkinson FL Brown MJ Chuang TT Christopher JA Cichy-Knight M Dunn AK Hightower KE Malkakorpi S Musgrave JR Neu M Rowland P Shea RL Smith JL Somers DO Thomas SA Thompson G Wang R 《Bioorganic & medicinal chemistry letters》2007,17(5):1296-1301
The identification and exploration of a novel, potent and selective series of N-(3-cyano-4,5,6,7-tetrahydro-1-benzothien-2-yl)amide inhibitors of JNK2 and JNK3 kinases is described. Compounds 5a and 11a were identified as potent inhibitors of JNK3 (pIC50 6.7 and 6.6, respectively), with essentially equal potency against JNK2 (pIC50 6.5). Selectivity within the mitogen-activated protein kinase (MAPK) family, against JNK1, p38alpha and ERK2, was observed for the series. X-ray crystallography of 5e and 8a in JNK3 revealed a unique binding mode, with the 3-cyano substituent forming an H-bond acceptor interaction with the hinge region of the ATP-binding site. 相似文献
3.
Song X Chen W Lin L Ruiz CH Cameron MD Duckett DR Kamenecka TM 《Bioorganic & medicinal chemistry letters》2011,21(23):7072-7075
The design and synthesis of a novel series of c-jun N-terminal kinase (JNK3) inhibitors is described. The development and optimization of the 2-phenoxypyridine series was carried out from an earlier pyrimidine series of JNK1 inhibitors. Through the optimization of the scaffold 2, several potent compounds with good in vivo profiles were discovered. 相似文献
4.
Noël R Shin Y Song X He Y Koenig M Chen W Ling YY Lin L Ruiz CH LoGrasso P Cameron MD Duckett DR Kamenecka TM 《Bioorganic & medicinal chemistry letters》2011,21(9):2732-2735
The design and synthesis of a novel series of c-jun N-terminal kinase (JNK) inhibitors is described. The development of the 4-(pyrazol-3-yl)-pyridine series was discovered from an earlier pyrimidine series of JNK inhibitors. Through the optimization of the scaffold 2, several potent compounds with good in vivo profiles were discovered. 相似文献
5.
Hom RK Bowers S Sealy JM Truong AP Probst GD Neitzel ML Neitz RJ Fang L Brogley L Wu J Konradi AW Sham HL Tóth G Pan H Yao N Artis DR Quinn K Sauer JM Powell K Ren Z Bard F Yednock TA Griswold-Prenner I 《Bioorganic & medicinal chemistry letters》2010,20(24):7303-7307
From high throughput screening, we discovered compound 1, the prototype for a series of disubstituted thiophene inhibitors of JNK which is selective towards closely related MAP kinases p38 and Erk2. Herein we describe the evolution of these compounds to a novel class of thiophene and thiazole JNK inhibitors that retain favorable solubility, permeability, and P-gp properties for development as CNS agents for treatment of neurodegeneration. Compound 61 demonstrated JNK3 IC(50)=77 nM and retained the excellent broad kinase selectivity observed for the series. 相似文献
6.
Rong Jiang Bozena Frackowiak Youseung Shin Xinyi Song Weimin Chen Li Lin Michael D. Cameron Derek R. Duckett Theodore M. Kamenecka 《Bioorganic & medicinal chemistry letters》2013,23(9):2683-2687
Starting from pyrazole HTS hit (1), a series of 1-aryl-1H-indazoles have been synthesized as JNK3 inhibitors with moderate selectivity against JNK1. SAR studies led to the synthesis of 5r as double digital nanomolar JNK3 inhibitor with good in vivo exposure. 相似文献
7.
Jingrong Cao Huai Gao Guy Bemis Francesco Salituro Mark Ledeboer Edmund Harrington Susanne Wilke Paul Taslimi S. Pazhanisamy Xiaoling Xie Marc Jacobs Jeremy Green 《Bioorganic & medicinal chemistry letters》2009,19(10):2891-2895
A series of N-benzylated isatin oximes were developed as inhibitors of the mitogen-activated kinase, JNK3. X-ray crystallographic structures aided in the design and synthesis of novel, selective compounds, that inhibit JNK3, but not p38 MAP kinase and provided key insights into understanding the behavior of gatekeeper residue methionine-146 in determining target selectivity for this series. 相似文献
8.
Asano Y Kitamura S Ohra T Aso K Igata H Tamura T Kawamoto T Tanaka T Sogabe S Matsumoto S Yamaguchi M Kimura H Itoh F 《Bioorganic & medicinal chemistry》2008,16(8):4715-4732
A novel series of 4-phenylisoquinolones were synthesized and evaluated as c-Jun N-terminal kinase (JNK) inhibitors. Initial modification at the 2- and 3-positions of the isoquinolone ring of hit compound 4, identified from high-throughput screening, led to the lead compound 6b. The optimization was carried out using a JNK1-binding model of 6b and several compounds exhibited potent JNK inhibition. Among them, 11g significantly inhibited cardiac hypertrophy in rat pressure-overload models without affecting blood pressure and the concept of JNK inhibitors as novel therapeutic agents for heart failure was confirmed. 相似文献
9.
Youseung Shin Weiming Chen Jeff Habel Derek Duckett Yuan Yuan Ling Marcel Koenig Yuanjun He Tomas Vojkovsky Philip LoGrasso Theodore M. Kamenecka 《Bioorganic & medicinal chemistry letters》2009,19(12):3344-3347
A novel series of c-jun N-terminal kinase (JNK) inhibitors were designed and developed from a high-throughput-screening hit. Through the optimization of the piperazine amide 1, several potent compounds were discovered. The X-ray crystal structure of 4g showed a unique binding mode different from other well known JNK3 inhibitors. 相似文献
10.
Asano Y Kitamura S Ohra T Itoh F Kajino M Tamura T Kaneko M Ikeda S Igata H Kawamoto T Sogabe S Matsumoto S Tanaka T Yamaguchi M Kimura H Fukumoto S 《Bioorganic & medicinal chemistry》2008,16(8):4699-4714
3-Metoxycarbonyl isoquinolone derivative 1 has been identified as a potent JNK inhibitor and significantly inhibited cardiac hypertrophy in a rat pressure-overload model. Herein, a series of isoquinolones with an imidazolylmethyl or a pyrazolylmethyl group at the 2-position were designed based on X-ray crystallographic analysis of the complex between the isoquinolone compound and JNK3, as wells as the relationship between compound lipophilicity (logD) and activity in a cell-based assay. The compounds prepared showed potent JNK1 inhibitory activities in a cell-based assay. Among them the isoquinolone derivative possessing 5-[(cyclopropylamino)carbonyl]-1-methyl-1H-pyrazole (16e) exhibited significant anti-hypertrophic activity at doses of more than 1mg/kg (po) in a pressure-overload model. 相似文献
11.
Jiang R Duckett D Chen W Habel J Ling YY LoGrasso P Kamenecka TM 《Bioorganic & medicinal chemistry letters》2007,17(22):6378-6382
The structure-based design and synthesis of a novel series of c-Jun N-terminal kinase (JNK) inhibitors with selectivity against p38 is reported. The unique structure of 3,5-disubstituted quinolines (2) was developed from the previously reported 4-(2,7-phenanthrolin-9-yl)phenol (1). The X-ray crystal structure of 16a in JNK3 reveals an unexpected binding mode for this new scaffold with protein. 相似文献
12.
Mitogen-activated protein kinases (MAPKs) are activated by numerous ligands typically through a protein kinase cascade minimally composed of the MAPK in series with a MAP2 kinase (MAP2K) and a MAP3K. This arrangement is thought to confer specificity and appropriate kinetic properties on the activation of MAPKs in response to physiological stimuli. Surprisingly, more than a dozen MAP3Ks have been identified that activate the c-Jun N-terminal kinases (JNKs) when overexpressed, but there is no clear understanding of which kinases actually mediate JNK activation by ligands. Here, we use double-stranded RNA-mediated interference of gene expression to reveal the explicit participation of discrete MAP3Ks in controlling JNK activity by multiple stimuli. Maximal activation of JNK by lipopolysaccharide requires the MAP3K TAK1. On the other hand, sorbitol requires expression of four MAP3Ks to cause maximal JNK activation. Thus, we demonstrate that specific stimuli use different mechanisms to recruit distinct MAP3Ks to regulate the JNK pathway. 相似文献
13.
Leyi Gong Xiaochun Han Tania Silva Yun-Chou Tan Bindu Goyal Parch Tivitmahaisoon Alejandra Trejo Wylie Palmer Heather Hogg Alam Jahagir Muzaffar Alam Paul Wagner Karin Stein Lubov Filonova Brad Loe Ferenc Makra David Rotstein Lubica Rapatova David Goldstein 《Bioorganic & medicinal chemistry letters》2013,23(12):3565-3569
A novel series of indole/indazole-aminopyrimidines was designed and synthesized with an aim to achieve optimal potency and selectivity for the c-Jun kinase family or JNKs. Structure guided design was used to optimize the series resulting in a significant potency improvement. The best compound (17) has IC50 of 3 nM for JNK1 and 20 nM for JNK2, with greater than 40-fold selectivity against other kinases with good physicochemical and pharmacokinetic properties. 相似文献
14.
John A. Christopher Francis L. Atkinson Benjamin D. Bax Murray J.B. Brown Aurélie C. Champigny Tsu Tshen Chuang Emma J. Jones Julie E. Mosley James R. Musgrave 《Bioorganic & medicinal chemistry letters》2009,19(8):2230-2234
A series of 1-aryl-3,4-dihydroisoquinoline inhibitors of JNK3 are described. Compounds 20 and 24 are the most potent inhibitors (pIC50 7.3 and 6.9, respectively in a radiometric filter binding assay), with 10- and 1000-fold selectivity over JNK2 and JNK1, respectively, and selectivity within the wider mitogen-activated protein kinase (MAPK) family against p38α and ERK2. X-ray crystallography of 16 reveals a highly unusual binding mode where an H-bond acceptor interaction with the hinge region is made by a chloro substituent. 相似文献
15.
Bowers S Truong AP Neitz RJ Neitzel M Probst GD Hom RK Peterson B Galemmo RA Konradi AW Sham HL Tóth G Pan H Yao N Artis DR Brigham EF Quinn KP Sauer JM Powell K Ruslim L Ren Z Bard F Yednock TA Griswold-Prenner I 《Bioorganic & medicinal chemistry letters》2011,21(6):1838-1843
The SAR of a series of tri-substituted thiophene JNK3 inhibitors is described. By optimizing both the N-aryl acetamide region of the inhibitor and the 4-position of the thiophene we obtained single digit nanomolar compounds, such as 47, which demonstrated an in vivo effect on JNK activity when dosed orally in our kainic acid mouse model as measured by phospho-c-jun reduction. 相似文献
16.
Surya K. De Vida Chen John L. Stebbins Li-Hsing Chen Jason F. Cellitti Thomas Machleidt Elisa Barile Megan Riel-Mehan Russell Dahl Li Yang Aras Emdadi Ria Murphy Maurizio Pellecchia 《Bioorganic & medicinal chemistry》2010,18(2):590-596
A series of thiadiazole derivatives has been designed as potential allosteric, substrate competitive inhibitors of the protein kinase JNK. We report on the synthesis, characterization and evaluation of a series of compounds that resulted in the identification of potent and selective JNK inhibitors targeting its JIP-1 docking site. 相似文献
17.
Alam M Beevers RE Ceska T Davenport RJ Dickson KM Fortunato M Gowers L Haughan AF James LA Jones MW Kinsella N Lowe C Meissner JW Nicolas AL Perry BG Phillips DJ Pitt WR Platt A Ratcliffe AJ Sharpe A Tait LJ 《Bioorganic & medicinal chemistry letters》2007,17(12):3463-3467
The development of a series of novel aminopyrimidines as inhibitors of c-Jun N-terminal kinases is described. The synthesis, in vitro inhibitory values for JNK1, JNK2 and CDK2, and the in vitro inhibitory value for a c-Jun cellular assay are discussed. 相似文献
18.
Peter Geuking Rajesh Narasimamurthy Bruno Lemaitre Konrad Basler Fran?ois Leulier 《PloS one》2009,4(11)
Background
The JNK pathway is a mitogen-activated protein (MAP) kinase pathway involved in the regulation of numerous physiological processes during development and in response to environmental stress. JNK activity is controlled by two MAPK kinases (MAPKK), Mkk4 and Mkk7. Mkk7 plays a prominent role upon Tumor Necrosis Factor (TNF) stimulation. Eiger, the unique TNF-superfamily ligand in Drosophila, potently activates JNK signaling through the activation of the MAPKKK Tak1.Methodology/Principal Findings
In a dominant suppressor screen for new components of the Eiger/JNK-pathway in Drosophila, we have identified an allelic series of the Mkk4 gene. Our genetic and biochemical results demonstrate that Mkk4 is dispensable for normal development and host resistance to systemic bacterial infection but plays a non-redundant role as a MAPKK acting in parallel to Hemipterous/Mkk7 in dTAK1-mediated JNK activation upon Eiger and Imd pathway activation.Conclusions/Significance
In contrast to mammals, it seems that in Drosophila both MAPKKs, Hep/Mkk7 and Mkk4, are required to induce JNK upon TNF or pro-inflammatory stimulation. 相似文献19.
S Neidhart B Antonsson C Gilliéron F Vilbois G Grenningloh S Arkinstall 《FEBS letters》2001,508(2):259-264
The neuronal growth-associated protein SCG10 is enriched in the growth cones of neurons where it destabilizes microtubules and thus contributes to the dynamic assembly and disassembly of microtubules. Since its microtubule-destabilizing activity is regulated by phosphorylation, SCG10 may link extracellular signals to rearrangements of the neuronal cytoskeleton. To identify signal transduction pathways that may lead to SCG10 phosphorylation, we tested a series of serine-threonine-directed protein kinases that phosphorylate SCG10 in vitro. We demonstrate that purified SCG10 can be phosphorylated by two subclasses of mitogen-activated protein (MAP) kinases, c-Jun N-terminal/stress-activated protein kinase (JNK/SAPK) and p38 MAP kinase. Moreover, SCG10 was found to bind tightly and specifically to JNK3/SAPKbeta. JNK3/SAPKbeta phosphorylation occurs at Ser-62 and Ser-73, residues that result in reduced microtubule-destabilizing activity for SCG10. Endogenous SCG10 also undergoes increased phosphorylation in sympathetic neurons at times of JNK3/SAPKbeta activation following deprivation from nerve growth factor. Together these observations indicate that activation of JNK/SAPKs provides a pathway for phosphorylation of SCG10 and control of growth cone microtubule formation following neuronal exposure to cellular stresses. 相似文献
20.
Surya K. De Li-Hsing Chen John L. Stebbins Thomas Machleidt Megan Riel-Mehan Russell Dahl Vida Chen Hongbin Yuan Elisa Barile Aras Emdadi Ria Murphy Maurizio Pellecchia 《Bioorganic & medicinal chemistry》2009,17(7):2712-2717
A new series of 2-thioether-benzothiazoles has been synthesized and evaluated for JNK inhibition. The SAR studies led to the discovery of potent, allosteric JNK inhibitors with selectivity against p38. 相似文献