共查询到20条相似文献,搜索用时 15 毫秒
1.
Tynebor RM Chen MH Natarajan SR O'Neill EA Thompson JE Fitzgerald CE O'Keefe SJ Doherty JB 《Bioorganic & medicinal chemistry letters》2011,21(1):411-416
The development and synthesis of potent p38α MAP kinase inhibitors containing a pyridazinone platform is described. Evolution of the p38α selective pyridopyridazin-6-one series from the p38α/β dual inhibitor 2H-quinolizin-2-one series will be discussed in full detail. 相似文献
2.
Amide-based inhibitors of p38α MAP kinase. Part 1: Discovery of novel N-pyridyl amide lead molecules
Gregory R. Luedtke Kurt Schinzel Xuefei Tan Richland W. Tester Imad Nashashibi Yong-jin Xu Sundeep Dugar Daniel E. Levy Joon Jung 《Bioorganic & medicinal chemistry letters》2010,20(8):2556-2559
A novel series of N-pyridyl amides as potent p38α kinase inhibitors is described. Based on the structural similarities between the initial hit and a well-known imidazole pyrimidine series of p38α inhibitors, potencies within the newly discovered series were quickly improved by installation of an (S)-α-methylbenzyl moiety at the 2-position of the pyridine ring. The proposed binding modes of the new series to p38α were evaluated against SAR findings and provided rationale for further development of this series of molecules. 相似文献
3.
Angell RM Angell TD Bamborough P Brown D Brown M Buckton JB Cockerill SG Edwards CD Jones KL Longstaff T Smee PA Smith KJ Somers DO Walker AL Willson M 《Bioorganic & medicinal chemistry letters》2008,18(1):324-328
The biphenyl amides are a novel series of p38 MAP kinase inhibitors. Structure-activity relationships of the series against p38alpha are discussed with reference to the X-ray crystal structure of an example. The series was optimised rapidly to a compound showing oral activity in an in vivo disease model. 相似文献
4.
Dombroski MA Letavic MA McClure KF Barberia JT Carty TJ Cortina SR Csiki C Dipesa AJ Elliott NC Gabel CA Jordan CK Labasi JM Martin WH Peese KM Stock IA Svensson L Sweeney FJ Yu CH 《Bioorganic & medicinal chemistry letters》2004,14(4):919-923
The synthesis and in vitro p38 alpha activity of a novel series of benzimidazolone inhibitors is described. The p38 alpha SAR is consistent with a mode of binding wherein the benzimidazolone carbonyl serves as the H-bond acceptor to Met109 of p38 alpha in a manner analogous to the pyridine nitrogen of prototypical pyridylimidazole p38 inhibitors. Potent p38 alpha activity comparable to that of several previously reported p38 inhibitors is observed for this novel chemotype. 相似文献
5.
Bullington J Argentieri D Averill K Carter D Cavender D Fahmy B Fan X Hall D Heintzelman G Jackson P Leung WP Li X Ling P Olini G Razler T Reuman M Rupert K Russell R Siekierka J Wadsworth S Wolff R Xiang B Zhang YM 《Bioorganic & medicinal chemistry letters》2006,16(23):6102-6106
Inhibition of the p38 map kinase pathway has been shown to be beneficial in the treatment of inflammatory diseases. The first class of potent p38 kinase inhibitors was the pyridinylimidazole compounds from SKB. Since then several pyridinylimidazole-based compounds have been shown to inhibit activated p38 kinase in vitro and in vivo. We have developed a novel series of pyridinylimidazole-based compounds, which potently inhibit the p38 pathway by binding to unactivated p38 kinase and only weakly inhibiting activated p38 kinase activity in vitro. 相似文献
6.
Wan Z Boehm JC Bower MJ Kassis S Lee JC Zhao B Adams JL 《Bioorganic & medicinal chemistry letters》2003,13(6):1191-1194
The design, synthesis and SAR of a series of 2,6,9-trisubstituted purine inhibitors of p38alpha kinase is reported. Synthetic routes were devised to allow for array synthesis in which all three points of diversity could be facilely explored. The binding of this novel series to p38alpha kinase, which was predicted to have several key interactions in common with SB-203580, was confirmed by X-ray crystallography of 19 (p38 IC(50)=82 nM). 相似文献
7.
Sawyer JS Beight DW Britt KS Anderson BD Campbell RM Goodson T Herron DK Li HY McMillen WT Mort N Parsons S Smith EC Wagner JR Yan L Zhang F Yingling JM 《Bioorganic & medicinal chemistry letters》2004,14(13):3581-3584
We have expanded our previously reported series of pyrazole-based inhibitors of the TGF-beta type I receptor kinase domain (TbetaR-I) to now include new 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole analogues. Limited examination of the SAR of this new series in both enzyme and cell based in vitro assays has revealed selectivity differences with respect to p38 MAP kinase (p38 MAPK) depending on the nature of the 'warhead' group on the dihydropyrrolopyrazole ring. As with our original pyrazole series, phenyl substituents tended to show greater selectivity against p38 MAPK than those comprised of the quinoline-4-yl moiety. We have also achieved co-crystallization and X-ray analysis of compounds 3 and 15, two potent examples of this new series, with the TbetaR-I receptor kinase domain. 相似文献
8.
Chen MH Fitzgerald P Singh SB O'Neill EA Schwartz CD Thompson CM O'Keefe SJ Zaller DM Doherty JB 《Bioorganic & medicinal chemistry letters》2008,18(6):2222-2226
Synthesis and biological activities of some quinolinone and dihydroquinolinone p38 MAP kinase inhibitors are reported. Modifications to the dihydroquinolinone pharmacophore revealed that dihydroquinolinone may be replaced with a quinolinone pharmacophore and lead to enhanced p38 inhibitory activity. From a study of C-7 substitutions by amino acid side chains, a very potent series of compounds in the p38 enzyme assays was identified. Translation of the in vitro activity into reasonable whole blood activity can be improved in this series of compounds by judicious modification of the physical properties at appropriate regions of the lead. 相似文献
9.
Laufer S Hauser D Stegmiller T Bracht C Ruff K Schattel V Albrecht W Koch P 《Bioorganic & medicinal chemistry letters》2010,20(22):6671-6675
The synthesis of 2,4,5-trisubstituted and 1,2,4,5-tetrasubstituted imidazoles as potent p38α mitogen-activated protein kinase inhibitors is described. The trisubstituted imidazole series was found to be more potent than the tetrasubstituted imidazole series. Many of these compounds show low-nanomolar activities in the isolated p38α MAP kinase inhibition assay. The structure-activity relationships between these two series are different and not comparable. 相似文献
10.
Stephen T. Wrobleski Shuqun Lin T.G. Murali Dhar Alaric J. Dyckman Tianle Li Sidney Pitt Rosemary Zhang Yi Fan Arthur M. Doweyko John S. Tokarski Kevin F. Kish Susan E. Kiefer John S. Sack John A. Newitt Mark R. Witmer Murray McKinnon Joel C. Barrish John H. Dodd Katerina Leftheris 《Bioorganic & medicinal chemistry letters》2013,23(14):4120-4126
A novel series of p38 MAP kinase inhibitors with high selectivity for the p38α isoform over the other family members including the highly homologous p38β isoform has been identified. X-ray co-crystallographic studies have revealed an unprecedented kinase binding mode in p38α for representative analogs, 5c and 9d, in which a Leu108/Met109 peptide flip occurs within the p38α hinge region. Based on these findings, a general strategy for the rational design of additional promising p38α isoform selective inhibitors by targeting this novel binding mode is proposed. 相似文献
11.
Brown DS Belfield AJ Brown GR Campbell D Foubister A Masters DJ Pike KG Snelson WL Wells SL 《Bioorganic & medicinal chemistry letters》2004,14(21):5383-5387
A novel p38 MAP kinase inhibitor structural class was discovered through selectivity screening. The rational analogue design, synthesis and structure-activity relationship of this series of bis-amide inhibitors is reported. The inhibition in vitro of human p38alpha enzyme activity and lipopolysaccharide-induced tumour necrosis factor-alpha release is described for the series. The activity in vivo and pharmacokinetic properties are exemplified for the more potent analogues. 相似文献
12.
Shaun R. Selness Rajesh V. Devraj Joseph B. Monahan Terri L. Boehm John K. Walker Balekudru Devadas Richard C. Durley Ravi Kurumbail Huey Shieh Li Xing Michael Hepperle Paul V. Rucker Kevin D. Jerome Alan G. Benson Laura D. Marrufo Heather M. Madsen Jeff Hitchcock Tom J. Owen Lance Christie Michele A. Promo Radhika Blevis-Bal 《Bioorganic & medicinal chemistry letters》2009,19(20):5851-5856
The identification and evolution of a series of potent and selective p38 inhibitors is described. p38 inhibitors based on a N-benzyl pyridinone high-throughput screening hit were prepared and their SAR explored. Their design was guided by ligand bound co-crystals of p38α. These efforts resulted in the identification of 12r and 19 as orally active inhibitors of p38 with significant efficacy in both acute and chronic models of inflammation. 相似文献
13.
Redman AM Johnson JS Dally R Swartz S Wild H Paulsen H Caringal Y Gunn D Renick J Osterhout M Kingery-Wood J Smith RA Lee W Dumas J Wilhelm SM Housley TJ Bhargava A Ranges GE Shrikhande A Young D Bombara M Scott WJ 《Bioorganic & medicinal chemistry letters》2001,11(1):9-12
Inhibitors of the MAP kinase p38 are potentially useful for the treatment for osteoporosis, arthritis, and other inflammatory diseases. A series of thienyl, furyl, and pyrrolyl ureas has been identified as potent p38 inhibitors, displaying in vitro activity in the nanomolar range. 相似文献
14.
Mavunkel BJ Chakravarty S Perumattam JJ Luedtke GR Liang X Lim D Xu YJ Laney M Liu DY Schreiner GF Lewicki JA Dugar S 《Bioorganic & medicinal chemistry letters》2003,13(18):3087-3090
p38alpha Mitogen Activated Protein Kinase (MAP kinase) is an intracellular soluble serine threonine kinase. p38alpha kinase is activated in response to cellular stresses, growth factors and cytokines such as interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-alpha). The central role of p38alpha activation in settings of both chronic and acute inflammation has led efforts to find inhibitors of this enzyme as possible therapies for diseases such as rheumatoid arthritis, where p38alpha activation is thought to play a causal role. Herein, we report structure-activity relationship studies on a series of indole-based heterocyclic inhibitors that led to the design and identification of a new class of p38alpha inhibitors. 相似文献
15.
Wrobleski ST Lin S Hynes J Wu H Pitt S Shen DR Zhang R Gillooly KM Shuster DJ McIntyre KW Doweyko AM Kish KF Tredup JA Duke GJ Sack JS McKinnon M Dodd J Barrish JC Schieven GL Leftheris K 《Bioorganic & medicinal chemistry letters》2008,18(8):2739-2744
A novel series of compounds based on the pyrrolo[2,1-f][1,2,4]triazine ring system have been identified as potent p38 alpha MAP kinase inhibitors. The synthesis, structure-activity relationships (SAR), and in vivo activity of selected analogs from this class of inhibitors are reported. Additional studies based on X-ray co-crystallography have revealed that one of the potent inhibitors from this series binds to the DFG-out conformation of the p38 alpha enzyme. 相似文献
16.
Kevin D. Jerome Paul V. Rucker Li Xing Huey S. Shieh John E. Baldus Shaun R. Selness Michael A. Letavic John F. Braganza Kim F. McClure 《Bioorganic & medicinal chemistry letters》2010,20(2):469-473
The structure based drug design, synthesis and structure–activity relationship of a series of C6 sulfur linked triazolopyridine based p38 inhibitors are described. The metabolic deficiencies of this series were overcome through changes in the C6 linker from sulfur to methylene, which was predicted by molecular modeling to be bioisosteric. X-ray of the ethylene linked compound 61 confirmed the predicted binding orientation of the scaffold in the p38 enzyme. 相似文献
17.
Shuqun Lin Stephen T. Wrobleski John Hynes Sidney Pitt Rosemary Zhang Yi Fan Arthur M. Doweyko Kevin F. Kish John S. Sack Mary F. Malley Susan E. Kiefer John A. Newitt Murray McKinnon James Trzaskos Joel C. Barrish John H. Dodd Gary L. Schieven Katerina Leftheris 《Bioorganic & medicinal chemistry letters》2010,20(19):5864-5868
The design, synthesis, and structure–activity relationships (SAR) of a series of 2-aminothiazol-5-yl-pyrimidines as novel p38α MAP kinase inhibitors are described. These efforts led to the identification of 41 as a potent p38α inhibitor that utilizes a unique nitrogen–sulfur intramolecular nonbonding interaction to stabilize the conformation required for binding to the p38α active site. X-ray crystallographic studies that confirm the proposed binding mode of this class of inhibitors in p38α and provide evidence for the proposed intramolecular nitrogen–sulfur interaction are discussed. 相似文献
18.
A series of potent p38 inhibitors based on the dihydroquinazoline scaffold was synthesized using a novel Pd-catalyzed cyclization reaction of aryl-benzyl ureas. Optimization of this compound class led to compound 20, which inhibits p38alpha in vitro with IC(50)=14 nM and is active in the mouse TNFalpha-release model. 相似文献
19.
20.
Hynes J Wu H Pitt S Shen DR Zhang R Schieven GL Gillooly KM Shuster DJ Taylor TL Yang X McIntyre KW McKinnon M Zhang H Marathe PH Doweyko AM Kish K Kiefer SE Sack JS Newitt JA Barrish JC Dodd J Leftheris K 《Bioorganic & medicinal chemistry letters》2008,18(6):1762-1767
A novel structural class of p38alpha MAP kinase inhibitors has been identified via iterative SAR studies of a focused deck screen hit. Optimization of the lead series generated 6e, BMS-640994, a potent and selective p38alpha inhibitor that is orally efficacious in rodent models of acute and chronic inflammation. 相似文献