共查询到20条相似文献,搜索用时 28 毫秒
1.
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
2.
Bowers S Truong AP Jeffrey Neitz R Hom RK Sealy JM Probst GD Quincy D Peterson B Chan W Galemmo RA Konradi AW Sham HL Tóth G Pan H Lin M Yao N Artis DR Zhang H Chen L Dryer M Samant B Zmolek W Wong K Lorentzen C Goldbach E Tonn G Quinn KP Sauer JM Wright S Powell K Ruslim L Ren Z Bard F Yednock TA Griswold-Prenner I 《Bioorganic & medicinal chemistry letters》2011,21(18):5521-5527
The SAR of a series of brain penetrant, trisubstituted thiophene based JNK inhibitors with improved pharmacokinetic properties is described. These compounds were designed based on information derived from metabolite identification studies which led to compounds such as 42 with lower clearance, greater brain exposure and longer half life compared to earlier analogs. 相似文献
3.
Kochanny MJ Adler M Ewing J Griedel BD Ho E Karanjawala R Lee W Lentz D Liang AM Morrissey MM Phillips GB Post J Sacchi KL Sakata ST Subramanyam B Vergona R Walters J White KA Whitlow M Ye B Zhao Z Shaw KJ 《Bioorganic & medicinal chemistry》2007,15(5):2127-2146
A series of thiophene-containing non-amidine factor Xa inhibitors is described. Simple methyl-substituted thiophene analogs were relatively weak inhibitors. However, introduction of hydrophilic substituents at C-4 or C-5 of the thiophene afforded inhibitors with low nanomolar potency. Optimization of the thiophene substituent at C-4 afforded subnanomolar inhibitors with improved in vitro anticoagulant activity. Incorporating basic amine substituents on the thiophene increased hydrophilicity and improved anticoagulant activity. The pharmacokinetic profile of one inhibitor was evaluated in dogs, and the X-ray crystal structure of this compound bound to factor Xa provides insight into the observed SAR for binding to factor Xa. 相似文献
4.
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
5.
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
6.
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
7.
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
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.
Pinkerton AB Lee TT Hoffman TZ Wang Y Kahraman M Cook TG Severance D Gahman TC Noble SA Shiau AK Davis RL 《Bioorganic & medicinal chemistry letters》2007,17(13):3562-3569
We have identified and synthesized a series of thiophene containing inhibitors of kinesin spindle protein. SAR studies led to the synthesis of 33, which was co-crystallized with KSP and determined to bind to an allosteric pocket previously described for other known KSP inhibitors. 相似文献
10.
Kumar GD Chavarria GE Charlton-Sevcik AK Yoo GK Song J Strecker TE Siim BG Chaplin DJ Trawick ML Pinney KG 《Bioorganic & medicinal chemistry letters》2010,20(22):6610-6615
A series of thiosemicarbazone analogs based on the benzophenone, thiophene, pyridine, and fluorene molecular frameworks has been prepared by chemical synthesis and evaluated as small-molecule inhibitors of the cysteine proteases cathepsin L and cathepsin B. The two most potent inhibitors of cathepsin L in this series (IC(50)<135 nM) are brominated-benzophenone thiosemicarbazone analogs that are further functionalized with a phenolic moiety (2 and 6). In addition, a bromo-benzophenone thiosemicarbazone acetyl derivative (3) is also strongly inhibitory against cathepsin L (IC(50)=150.8 nM). Bromine substitution in the thiophene series results in compounds that demonstrate only moderate inhibition of cathepsin L. The two most active analogs in the benzophenone thiosemicarbazone series are highly selective for their inhibition of cathepsin L versus cathepsin B. 相似文献
11.
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
12.
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
13.
Swahn BM Huerta F Kallin E Malmström J Weigelt T Viklund J Womack P Xue Y Ohberg L 《Bioorganic & medicinal chemistry letters》2005,15(22):5095-5099
The structure-based design and synthesis of a new series of c-Jun N-terminal kinase-3 inhibitors with selectivity against JNK1 and p38alpha is reported. The novel series of substituted 6-anilinoindazoles were designed based on a combination of hits from high throughput screening and X-ray crystal structure information of the compounds crystallized into the JNK3 ATP binding active site. 相似文献
14.
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
15.
Wickens P Kluender H Dixon J Brennan C Achebe F Bacchiocchi A Bankston D Bierer D Brands M Braun D Brown MS Chuang CY Dumas J Enyedy I Hofilena G Hong Z Housley T Jones B Khire U Kreiman C Kumarasinghe E Lowinger T Ott-Morgan R Perkins L Phillips B Schoenleber R Scott WJ Sheeler R Redman A Sun X Taylor I Wang L Wilhelm S Zhang X Zhang M Sullivan E Carter C Miglarese M Levy J 《Bioorganic & medicinal chemistry letters》2007,17(15):4378-4381
Novel anthranilamides were surprisingly found to exert additional activity on B-RAF. Corresponding thiophene, pyrazole, and thiazole core analogs were prepared as VEGFR-2 inhibitors with c-KIT, and B-RAF activity. Compounds in the phenyl, thiophene, and thiazole series are in vivo active. 相似文献
16.
Liu M Wang S Clampit JE Gum RJ Haasch DL Rondinone CM Trevillyan JM Abad-Zapatero C Fry EH Sham HL Liu G 《Bioorganic & medicinal chemistry letters》2007,17(3):668-672
A new series of 4-anilinopyrimidines has been synthesized and evaluated as JNK1 inhibitors. SAR studies led to the discovery of potent JNK1 inhibitors with good enzymatic activity as well as cellular potency represented by compound 2b. Kinase selectivity profile and the crystal structure of 2b are also described. 相似文献
17.
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
18.
Kyle A. Emmitte George M. Adjebang C. Webb Andrews Jennifer G. Badiang Alberti Ramesh Bambal Stanley D. Chamberlain Ronda G. Davis-Ward Hamilton D. Dickson Daniel F. Hassler Keith R. Hornberger Jeffrey R. Jackson Kevin W. Kuntz Timothy J. Lansing Robert A. Mook Kristen E. Nailor Mark A. Pobanz Stephon C. Smith Chiu-Mei Sung Mui Cheung 《Bioorganic & medicinal chemistry letters》2009,19(6):1694-1697
A series of thiophene PLK1 inhibitors was optimized for increased solubility and reduced protein binding through the appendage of basic amine functionality. Interesting selectivity between PLK1 and PLK3 was also obtained through these modifications. 相似文献
19.
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
20.
Qinghua Wu Wenda Wu Vesna Jacevic Tanos C. C. Franca 《Journal of enzyme inhibition and medicinal chemistry》2013,28(1):574-583
Abstract c-Jun N-terminal kinase (JNK) signalling regulates both cancer cell apoptosis and survival. Emerging evidence show that JNK promoted tumour progression is involved in various cancers, that include human pancreatic-, lung-, and breast cancer. The pro-survival JNK oncoprotein functions in a cell context- and cell type-specific manner to affect signal pathways that modulate tumour initiation, proliferation, and migration. JNK is therefore considered a potential oncogenic target for cancer therapy. Currently, designing effective and specific JNK inhibitors is an active area in the cancer treatment. Some ATP-competitive inhibitors of JNK, such as SP600125 and AS601245, are widely used in vitro; however, this type of inhibitor lacks specificity as they indiscriminately inhibit phosphorylation of all JNK substrates. Moreover, JNK has at least three isoforms with different functions in cancer development and identifying specific selective inhibitors is crucial for the development of targeted therapy in cancer. Some selective inhibitors of JNK are identified; however, their clinical studies in cancer are relatively less conducted. In this review, we first summarised the function of JNK signalling in cancer progression; there is a focus on the discussion of the novel selective JNK inhibitors as potential targeting therapy in cancer. Finally, we have offered a future perspective of the selective JNK inhibitors in the context of cancer therapies. We hope this review will help to further understand the role of JNK in cancer progression and provide insight into the design of novel selective JNK inhibitors in cancer treatment. 相似文献