共查询到20条相似文献,搜索用时 15 毫秒
1.
L W Daniel G W Small J D Schmitt C J Marasco K Ishaq C Piantadosi 《Biochemical and biophysical research communications》1988,151(1):291-297
Alkylacylglycerols are synthesized when choline-phospholipids are degraded by a phospholipase C. This class of compounds has been shown to have biological activities; however, the mechanism of action is unknown. A series of alkyl-linked diglycerides were synthesized and tested for activity in an in vitro assay for protein kinase C. When protein kinase C activity was stimulated with the synthetic diacylglyceride analog 1-oleoyl-2-acetyl-sn-glycerol, the addition of alkyl glycerides caused a concentration-dependent inhibition of protein kinase C activity. Comparison of the protein kinase C inhibition by this series of 1-O-alkyl-2-acyl analogs revealed that both saturated and unsaturated long-chain groups in position 1 were effective and that dietherglycerols with short-chain moieties in position 2 were also effective. It is concluded from these studies that the biological activity of alkyl-linked glycerides may be expressed through protein kinase C inhibition. 相似文献
2.
Asano T Yoshikawa T Nakamura H Uehara Y Yamamoto Y 《Bioorganic & medicinal chemistry letters》2004,14(9):2299-2302
The benzamides 1 and the benzamidines 2-3 were synthesized as the mimics of 4-anilinoquinazolines, which possess inhibition of epidermal growth factor receptor (EGFR) tyrosine kinase, and tested for cytotoxicity toward A431 and inhibitory activity toward autophosphorylation by the enzyme assay. High cell growth inhibition was observed in a series of the cyclic benzamides 3: the IC(50) values are 0.09-0.32 mM. The benzamidines 3a and 3b exhibited high inhibition of EGFR tyrosine kinase at a 1.0 microM concentration, although the benzamides 1 and the benzamidines 2 did not show significant kinase inhibition at a 10 microM concentration. 相似文献
3.
Bode CM Boezio AA Albrecht BK Bellon SF Berry L Broome MA Choquette D Dussault I Lewis RT Lin MH Rex K Whittington DA Yang Y Harmange JC 《Bioorganic & medicinal chemistry letters》2012,22(12):4089-4093
Deregulation of the receptor tyrosine kinase c-Met has been implicated in several human cancers and is an attractive target for small molecule drug discovery. Herein, we report the discovery of a structurally diverse series of carbon-linked quinoline triazolopyridinones, which demonstrates nanomolar inhibition of c-Met kinase activity. This novel series of inhibitors exhibits favorable pharmacokinetics as well as potent inhibition of HGF-mediated c-Met phosphorylation in a mouse liver pharmacodynamic model. 相似文献
4.
Mortensen DS Perrin-Ninkovic SM Harris R Lee BG Shevlin G Hickman M Khambatta G Bisonette RR Fultz KE Sankar S 《Bioorganic & medicinal chemistry letters》2011,21(22):6793-6799
We report here the discovery of a novel series of selective mTOR kinase inhibitors. A series of imidazo[4,5-b]pyrazin-2-ones, represented by screening hit 1, was developed into lead compounds with excellent mTOR potency and exquisite kinase selectivity. Potent compounds from this series show >1000-fold selectivity over the related PI3Kα lipid kinase. Further, compounds such as 2 achieve mTOR pathway inhibition, blocking both mTORC1 and mTORC2 signaling, in PC3 cancer cells as measured by inhibition of pS6 and pAkt (S473). 相似文献
5.
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
6.
Theodore C. Jessop James E. Tarver Marianne Carlsen Amy Xu Jason P. Healy Alexander Heim-Riether Qinghong Fu Jerry A. Taylor David J. Augeri Min Shen Terry R. Stouch Ronald V. Swanson Leslie W. Tari Michael Hunter Isaac Hoffman Philip E. Keyes Xuan-Chuan Yu Maricar Miranda Qingyun Liu Jonathan C. Swaffield Kenneth G. Carson 《Bioorganic & medicinal chemistry letters》2009,19(23):6784-6787
A series of deoxycytidine kinase inhibitors was simultaneously optimized for potency and PK properties. A co-crystal structure then allowed merging this series with a high throughput screening hit to afford a highly potent, selective and orally bioavailable inhibitor, compound 10. This compound showed dose dependent inhibition of deoxycytidine kinase in vivo. 相似文献
7.
Qingping Zeng Matthew P. Bourbeau G. Erich Wohlhieter Guomin Yao Holger Monenschein James T. Rider Matthew R. Lee Shiwen Zhang Julie Lofgren Daniel Freeman Chun Li Elizabeth Tominey Xin Huang Douglas Hoffman Harvey Yamane Andrew S. Tasker Celia Dominguez Vellarkad N. Viswanadhan Randall Hungate Xiaoling Zhang 《Bioorganic & medicinal chemistry letters》2010,20(5):1652-1656
A series of 2-aminothiadiazole of inhibitors of AKT1 is described. SAR relationships are discussed, along with selectivity for protein kinase A (PKA) and cyclin-dependent kinase 2 (CDK2). Moderate selectivity observed in several compounds for AKT1 versus PKA is rationalized by X-ray crystallographic analysis. Key compounds showed activity in cellular assays measuring phosphorylation of two AKT substrates, PRAS40 and FKHRL1. Compound 30 was advanced to a mouse liver PD assay, where it showed dose-dependent inhibition of AKT activity, as measured by the inhibition of phospho-PRAS40. 相似文献
8.
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
9.
Alessandro A. Boezio Loren Berry Brian K. Albrecht David Bauer Steven F. Bellon Christiane Bode April Chen Deborah Choquette Isabelle Dussault Satoko Hirai Paula Kaplan-Lefko Jay F. Larrow Min-Hwa Jasmine Lin Julia Lohman Michele H. Potashman Karen Rex Michael Santostefano Kavita Shah Roman Shimanovich Stephanie K. Springer Yohannes Teffera Yajing Yang Yihong Zhang Jean-Christophe Harmange 《Bioorganic & medicinal chemistry letters》2009,19(22):6307-6312
Deregulation of the receptor tyrosine kinase c-Met has been implicated in several human cancers and is an attractive target for small molecule drug discovery. We previously showed that O-linked triazolopyridazines can be potent inhibitors of c-Met. Herein, we report the discovery of a related series of N-linked triazolopyridazines which demonstrate nanomolar inhibition of c-Met kinase activity and display improved pharmacodynamic profiles. Specifically, the potent time-dependent inhibition of cytochrome P450 associated with the O-linked triazolopyridazines has been eliminated within this novel series of inhibitors. N-linked triazolopyridazine 24 exhibited favorable pharmacokinetics and displayed potent inhibition of HGF-mediated c-Met phosphorylation in a mouse liver PD model. Once-daily oral administration of 24 for 22 days showed significant tumor growth inhibition in an NIH-3T3/TPR-Met xenograft mouse efficacy model. 相似文献
10.
Curtin ML Frey RR Heyman HR Sarris KA Steinman DH Holmes JH Bousquet PF Cunha GA Moskey MD Ahmed AA Pease LJ Glaser KB Stewart KD Davidsen SK Michaelides MR 《Bioorganic & medicinal chemistry letters》2004,14(17):4505-4509
A series of substituted isoindolinone ureas was prepared and evaluated for enzymatic and cellular inhibition of KDR kinase activity. Several of these analogs, such as 14c, are potent inhibitors of KDR both enzymatically (< 50 nM) and cellularly < or = 100 nM). A 3D KDR/CDK2/MAP kinase overlay model with several structurally related tyrosine kinase inhibitors was used to predict the binding interactions of the isoindolinone ureas with the KDR active site. 相似文献
11.
Lippa B Pan G Corbett M Li C Kauffman GS Pandit J Robinson S Wei L Kozina E Marr ES Borzillo G Knauth E Barbacci-Tobin EG Vincent P Troutman M Baker D Rajamohan F Kakar S Clark T Morris J 《Bioorganic & medicinal chemistry letters》2008,18(11):3359-3363
Based on a high throughput screening hit, pyrrolopyrimidine inhibitors of the Akt kinase are explored. X-ray co-crystal structures of two lead series results in the understanding of key binding interactions, the design of new lead series, and enhanced potency. The syntheses of these series and their biological activities are described. Spiroindoline 13j is found to have an Akt1 kinase IC(50) of 2.4+/-0.6 nM, Akt cell potency of 50+/-19 nM, and provides 68% inhibition of tumor growth in a mouse xenograft model (50 mg/kg, qd, po). 相似文献
12.
Four series of dihydropyrazolo[3,4-b]pyridines and benzo[4,5]imidazo[1,2-a]pyrimidines were designed and synthesized as dual KSP and Aurora-A kinase inhibitors for anti-cancer agents by introducing some fragments of Aurora-A kinase inhibitors into our KSP inhibitor CPUYL064. A total of 19 target compounds were evaluated by two related enzyme inhibition assays and a cytotoxicity assay in vitro. The results showed that some target compounds could inhibit both enzymes, and several of them showed significant inhibition activity against HCT116 cell line. Despite showing moderate KSP and Aurora-A kinase inhibition, the lead compounds 6a and 6e displayed significant cytotoxic activity in the micromolar range, especially against the HCT116 cell line and HepG2 cell line. The results may be useful for developing a new class of inhibitors having a dual function, KSP inhibition and Aurora-A kinase inhibition, for the treatment of cancer. 相似文献
13.
Oslob JD Romanowski MJ Allen DA Baskaran S Bui M Elling RA Flanagan WM Fung AD Hanan EJ Harris S Heumann SA Hoch U Jacobs JW Lam J Lawrence CE McDowell RS Nannini MA Shen W Silverman JA Sopko MM Tangonan BT Teague J Yoburn JC Yu CH Zhong M Zimmerman KM O'Brien T Lew W 《Bioorganic & medicinal chemistry letters》2008,18(17):4880-4884
This communication describes the discovery of a novel series of Aurora kinase inhibitors. Key SAR and critical binding elements are discussed. Some of the more advanced analogues potently inhibit cellular proliferation and induce phenotypes consistent with Aurora kinase inhibition. In particular, compound 21 (SNS-314) is a potent and selective Aurora kinase inhibitor that exhibits significant activity in pre-clinical in vivo tumor models. 相似文献
14.
Wissner A Brawner Floyd MB Rabindran SK Nilakantan R Greenberger LM Shen R Wang YF Tsou HR 《Bioorganic & medicinal chemistry letters》2002,12(20):2893-2897
The syntheses and biological evaluations of 4-anilinoquinoline-3-carbonitrile analogues of the three clinical lead 4-anilinoquinazolines Iressa, Tarceva, and CI-1033 are described. The EGFR and HER-2 kinase inhibitory activities and the cell growth inhibition of the two series are compared with each other and with the clinical lead EKB-569. Similar activities are observed between these two series. 相似文献
15.
Zhang N Wu B Wissner A Powell DW Rabindran SK Kohler C Boschelli F 《Bioorganic & medicinal chemistry letters》2002,12(3):423-425
A series of 4-anilino-3-cyanobenzo[g]quinolines was prepared as potent kinase inhibitors. Compared with their bicyclic 4-anilino-3-cyanoquinoline analogues, the tricyclic 4-anilino-3-cyanobenzo[g]quinolines are less active against EGF-R kinase, equally active against MAPK kinase (MEK), and more active against Src kinase. For Src kinase inhibition, the best activity is obtained when both the 7- and 8-positions are substituted with alkoxy groups. Several of these kinase inhibitors show potent growth inhibitory activity in tumor cells. 相似文献
16.
Noel A. Powell Jennifer K. Hoffman Fred L. Ciske Michael D. Kaufman Jeffrey T. Kohrt John Quin Derek J. Sheehan Amy Delaney Sangita M. Baxi Cornel Catana Patrick McConnell Jeff Ohren Lisa A. Perrin Jeremy J. Edmunds 《Bioorganic & medicinal chemistry letters》2013,23(4):1046-1050
We report the SAR around a series of 2,4-diaminopyrimidine-5-carboxamide inhibitors of Sky kinase. 2-Aminophenethyl analogs demonstrate excellent potency but moderate kinase selectivity, while 2-aminobenzyl analogs that fill the Ala571 subpocket exhibit good inhibition activity and excellent kinase selectivity. 相似文献
17.
Richard Ducray Clifford D. JonesFrederic H. Jung Iain SimpsonJon Curwen Martin Pass 《Bioorganic & medicinal chemistry letters》2011,21(16):4702-4704
Following the discovery of imidazopyridine 1 as a potent IGF-1R tyrosine kinase inhibitor, the aniline part has been modified with the aim to optimize the properties of this series. The structure-activity relationships against IGF-1R kinase activity as well as inhibition of the hERG ion channel are discussed. 相似文献
18.
Abraham S Hadd MJ Tran L Vickers T Sindac J Milanov ZV Holladay MW Bhagwat SS Hua H Ford Pulido JM Cramer MD Gitnick D James J Dao A Belli B Armstrong RC Treiber DK Liu G 《Bioorganic & medicinal chemistry letters》2011,21(18):5296-5300
The synthesis and SAR for a novel series of pyrrolotriazines as pan-Aurora kinase inhibitors are described. Optimization of the cyclopropane carboxamide terminus of lead compound 1 resulted in analogs with high cellular activity and improved rat PK profiles. Notably, compound 17l demonstrated tumor growth inhibition in a mouse xenograft model. 相似文献
19.
《The International journal of biochemistry》1994,26(10-11):1203-1226
The various aspects of the research on tyrosine protein kinase inhibition and its connections with cancer are presented. The emphasis was made on the theoretical low toxic side effects of specific tyrosine protein kinase inhibitors. Particularly, the strategy of finding peptidic substrate-derived inhibitors or modulators is discussed, with an almost complete compendium of the tyrosine protein kinase peptidic substrates published so far. A series of data has been gathered that may serve as a basis for the discovery of selective and specific tyrosine protein kinase inhibitors by screening on molecular and cellular models. The potential of SH2 domain-interfering agents are also presented as a promising route to new anticancer compounds. 相似文献
20.
《Journal of enzyme inhibition and medicinal chemistry》2013,28(2):158-171
Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor-2 (VEGFR-2), two protein tyrosine kinases, are involved in pathological disorders and the progression of different types of carcinomas. Concomitant inhibition of both tyrosine kinase activities appears to be an attractive target for cancer chemotherapy. A series of new quinazoline derivatives substituted by amide, urea, or carbamic acid ester groups have been synthesized. The biological activities of these new compounds have been evaluated for their enzyme inhibition and antiproliferative activities. 相似文献