共查询到20条相似文献,搜索用时 33 毫秒
1.
Aiguadé J Balagué C Carranco I Caturla F Domínguez M Eastwood P Esteve C González J Lumeras W Orellana A Preciado S Roca R Vidal L Vidal B 《Bioorganic & medicinal chemistry letters》2012,22(10):3431-3436
A new class of p38α inhibitors based on a biaryl-triazolopyridine scaffold was investigated. X-ray crystallographic data of the initial lead compound cocrystallised with p38α was crucial in order to uncover a unique binding mode of the inhibitor to the hinge region via a pair of water molecules. Synthesis and SAR was directed towards the improvement of binding affinity, as well as ADME properties for this new class of p38α inhibitors and ultimately afforded compounds showing good in vivo efficacy. 相似文献
2.
Liu C Lin J Pitt S Zhang RF Sack JS Kiefer SE Kish K Doweyko AM Zhang H Marathe PH Trzaskos J Mckinnon M Dodd JH Barrish JC Schieven GL Leftheris K 《Bioorganic & medicinal chemistry letters》2008,18(6):1874-1879
Rational design, synthesis, and SAR studies of a novel class of benzothiazole based inhibitors of p38alpha MAP kinase are described. The issue of metabolic instability associated with vicinal phenyl, benzo[d]thiazol-6-yl oxazoles/imidazoles was addressed by the replacement of the central oxazole or imidazole ring with an aminopyrazole system. The proposed binding mode of this new class of p38alpha inhibitors was confirmed by X-ray crystallographic studies of a representative inhibitor (6a) bound to the p38alpha enzyme. 相似文献
3.
Moffett K Konteatis Z Nguyen D Shetty R Ludington J Fujimoto T Lee KJ Chai X Namboodiri H Karpusas M Dorsey B Guarnieri F Bukhtiyarova M Springman E Michelotti E 《Bioorganic & medicinal chemistry letters》2011,21(23):7155-7165
Discovery of a new class of DFG-out p38α kinase inhibitors with no hinge interaction is described. A computationally assisted, virtual fragment-based drug design (vFBDD) platform was utilized to identify novel non-aromatic fragments which make productive hydrogen bond interactions with Arg 70 on the αC-helix. Molecules incorporating these fragments were found to be potent inhibitors of p38 kinase. X-ray co-crystal structures confirmed the predicted binding modes. A lead compound was identified as a potent (p38α IC(50)=22 nM) and highly selective (≥ 150-fold against 150 kinase panel) DFG-out p38 kinase inhibitor. 相似文献
4.
The p38 MAP kinase is implicated in the release of the pro-inflammatory cytokines TNFα and IL-1b. Inhibition of cytokine release may be a useful treatment for inflammatory conditions such as rheumatoid arthritis and Crohn’s disease. A new lead structure for p38 MAP kinase inhibition was identified. Herein, we report the SAR of this new class of p38 inhibitors. 相似文献
5.
Dumas J Hatoum-Mokdad H Sibley R Riedl B Scott WJ Monahan MK Lowinger TB Brennan C Natero R Turner T Johnson JS Schoenleber R Bhargava A Wilhelm SM Housley TJ Ranges GE Shrikhande A 《Bioorganic & medicinal chemistry letters》2000,10(18):2051-2054
Inhibitors of the MAP kinase p38 are potentially useful for the treatment of arthritis and osteoporosis. Several 2,3-dichlorophenyl ureas were identified as small-molecule inhibitors of p38 by a combinatorial chemistry effort. Optimization for cellular potency led to the discovery of a new class of potent and selective p38 kinase inhibitors, exemplified by the 1-phenyl-5-pyrazolyl urea 7 (IC50 = 13 nM). 相似文献
6.
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
7.
Cogan DA Aungst R Breinlinger EC Fadra T Goldberg DR Hao MH Kroe R Moss N Pargellis C Qian KC Swinamer AD 《Bioorganic & medicinal chemistry letters》2008,18(11):3251-3255
A computer-aided drug design strategy leads to the identification of a new class of p38 inhibitors based on the 2-tolyl-(1,2,3-triazol-1-yl-4-carboxamide) scaffold. The tolyl triazole amides provided a potent platform amenable to optimization. Further exploration leads to compounds with greater than 100-fold improvement in binding affinity to p38. Derivatives prepared to alter the physicochemical properties produced inhibitors with IC(50)'s in human whole blood as low as 83 nM. 相似文献
8.
Natarajan SR Wisnoski DD Singh SB Stelmach JE O'Neill EA Schwartz CD Thompson CM Fitzgerald CE O'Keefe SJ Kumar S Hop CE Zaller DM Schmatz DM Doherty JB 《Bioorganic & medicinal chemistry letters》2003,13(2):273-276
A new class of p38 antagonists based on 3,4-dihydropyrido[3,2,-d]pyrimidine scaffold has been developed. These inhibitors exhibit unprecedented selectivity towards p38 over other very closely related kinases. Compounds 25, 33, and 34 were identified as benchmark analogues for follow-up studies. They show good potency for enzyme inhibition and excellent functional activity. 相似文献
9.
New modifications to the area of pyrazole-naphthyl urea based p38 MAP kinase inhibitors that bind to the adenine/ATP site 总被引:1,自引:0,他引:1
Moss N Breitfelder S Betageri R Cirillo PF Fadra T Hickey ER Kirrane T Kroe RR Madwed J Nelson RM Pargellis CA Qian KC Regan J Swinamer A Torcellini C 《Bioorganic & medicinal chemistry letters》2007,17(15):4242-4247
Discovery of the pyrazole-naphthyl urea class of p38 MAP kinase inhibitors typified by the clinical candidate BIRB 796 has encouraged further exploration of this particular scaffold. Modification to the part of the inhibitor that occupies the adenine/ATP binding site has resulted in a new way to obtain potent inhibitors that possess favorable in vitro and in vivo properties. 相似文献
10.
Dumas J Sibley R Riedl B Monahan MK Lee W Lowinger TB Redman AM Johnson JS Kingery-Wood J Scott WJ Smith RA Bobko M Schoenleber R Ranges GE Housley TJ Bhargava A Wilhelm SM Shrikhande A 《Bioorganic & medicinal chemistry letters》2000,10(18):2047-2050
The MAP kinase p38 has been implicated in cytokine signaling, and its inhibitors are potentially useful for the treatment of arthritis and osteoporosis. Novel small-molecule inhibitors of p38 kinase were derived from a combinatorial chemistry effort and exhibit activity in the nanomolar range. Very steep structure-activity relationships are observed within this class. 相似文献
11.
Babu J. Mavunkel John J. Perumattam Xuefei Tan Gregory R. Luedtke Qing Lu Don Lim Darin Kizer Sundeep Dugar Sarvajit Chakravarty Yong-jin Xu Joon Jung Albert Liclican Daniel E. Levy Jocelyn Tabora 《Bioorganic & medicinal chemistry letters》2010,20(3):1059-1062
The design and synthesis of a new class of p38α MAP kinase inhibitors based on 4-fluorobenzylpiperidine heterocyclic oxalyl amides are described. Many of these compounds showed low-nanomolar activities in p38α enzymatic and cell-based cytokine TNFα production inhibition assays. The optimal linkers between the piperidine and the oxalyl amide were found to be [6,5] fused ring heterocycles. Substituted indoles and azaindoles were favored structural motifs in the cellular assay. 相似文献
12.
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
13.
Brugel TA Maier JA Clark MP Sabat M Golebiowski A Bookland RG Laufersweiler MJ Laughlin SK Vanrens JC De B Hsieh LC Mekel MJ Janusz MJ 《Bioorganic & medicinal chemistry letters》2006,16(13):3510-3513
A new class of tumor necrosis factor alpha (TNF-alpha) synthesis inhibitors based on an N-2,4-pyrimidine-N-phenyl-N'-phenyl urea scaffold is described. Many of these compounds showed low-nanomolar activity against lipopolysaccharide stimulated TNF-alpha production. X-ray co-crystallization studies with mutated p38alpha showed that these trisubstituted ureas interact with the ATP-binding pocket in a pseudo-bicyclic conformation brought about by the presence of an intramolecular hydrogen bonding interaction. 相似文献
14.
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
15.
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
16.
Liu L Stelmach JE Natarajan SR Chen MH Singh SB Schwartz CD Fitzgerald CE O'Keefe SJ Zaller DM Schmatz DM Doherty JB 《Bioorganic & medicinal chemistry letters》2003,13(22):3979-3982
Development for a class of potent 3,4-dihydropyrido(3,2-d)pyrimidone inhibitors of p38a MAP kinase is described. Modification of N-1 aryl and C-6 arylsulfide in 3,4-dihydropyrido(3,2-d)pyrimidone analogues for the interaction with the hydrophobic pockets in p38 active site is also discussed. 相似文献
17.
Jing Li Tamer S. Kaoud Christophe Laroche Kevin N. Dalby Sean M. Kerwin 《Bioorganic & medicinal chemistry letters》2009,19(22):6293-6297
Based on the mild, thermal rearrangement of 1,2-dialkynylimidazoles to reactive carbene or diradical intermediates, a series of 1,2-dialkynylimidazoles were designed as potential irreversible p38 MAP kinase α-isoform (p38α) inhibitors. The synthesis of these dialkynylimidazoles and their kinase inhibition activity is reported. The 1-ethynyl-substituted dialkynylimidazole 14 is a potent (IC50 = 200 nM) and selective inhibitor of p38α. Moreover, compound 14 covalently modifies p38α as determined by ESI-MS after 12 h incubation at 37 °C. The unique kinase inhibition, covalent kinase adduct formation, and minimal CYP450 2D6 inhibition by compound 14 demonstrate that dialkynylimidazoles are a new, promising class of p38α inhibitors. 相似文献
18.
Kim J Kim HR Lee JC Jang YS 《Biochemical and biophysical research communications》2002,291(1):139-145
Substantial evidence suggests that MHC class II molecules play a critical role in transducing signals during B cell activation and differentiation. In addition, we previously found that cross-linking of MHC class II molecules using anti-MHC class II antibodies inhibited NF-kappaB activation in resting B cells isolated from mouse spleen. In this study, we investigated the mechanism of anti-MHC class II antibody-mediated inhibition of LPS-induced NF-kappaB activation using a resting B cell line, 38B9. We found that treatment with a corresponding anti-MHC class II antibody reduced the activation of NF-kappaB in LPS-stimulated 38B9 cells, treatment of the antibody mediated down-regulation of PKC and ERK/p38 MAP kinase pathways, and treatment with PKC inhibitors caused down-regulation of ERK and p38 MAP kinase activities in LPS-stimulated 38B9 cells. Our results suggest that the PKC and ERK/p38 MAP kinase pathways are regulated by anti-MHC class II antibodies, and that MHC class II molecules are actively involved in the signal transduction pathway in the resting B cell line, 38B9. Consequently, disruption of these pathways might contribute to the inhibition of LPS-induced NF-kappaB activation in 38B9 cells. 相似文献
19.
Somwar R Koterski S Sweeney G Sciotti R Djuric S Berg C Trevillyan J Scherer PE Rondinone CM Klip A 《The Journal of biological chemistry》2002,277(52):50386-50395
Participation of p38 mitogen-activated protein kinase (p38) in insulin-induced glucose uptake was suggested using pyridinylimidazole p38 inhibitors (e.g. SB203580). However, the role of p38 in insulin action remains controversial. We further test p38 participation in glucose uptake using a dominant-negative p38 mutant and two novel pharmacological p38 inhibitors related to but different from SB203580. We present the structures and activities of the azaazulene pharmacophores A291077 and A304000. p38 kinase activity was inhibited in vitro by A291077 and A304000 (IC(50) = 0.6 and 4.7 microm). At higher concentrations A291077 but not A304000 inhibited JNK2alpha (IC(50) = 3.5 microm). Pretreatment of 3T3-L1 adipocytes and L6 myotubes expressing GLUT4myc (L6-GLUT4myc myotubes) with A291077, A304000, SB202190, or SB203580 reduced insulin-stimulated glucose uptake by 50-60%, whereas chemical analogues inert toward p38 were ineffective. Expression of an inducible, dominant-negative p38 mutant in 3T3-L1 adipocytes reduced insulin-stimulated glucose uptake. GLUT4 translocation to the cell surface, immunodetected on plasma membrane lawns of 3T3-L1 adipocytes or on intact L6-GLUT4myc myotubes, was not altered by chemical or molecular inhibition of p38. We propose that p38 contributes to enhancing GLUT4 activity, thereby increasing glucose uptake. In addition, the azaazulene class of inhibitors described will be useful to decipher cellular actions of p38 and JNK. 相似文献
20.
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