共查询到20条相似文献,搜索用时 15 毫秒
1.
Lori M. Miller Scott C. Mayer Dan M. Berger Diane H. Boschelli Frank Boschelli Li Di Xuemei Du Minu Dutia Middleton B. Floyd Mark Johnson Cynthia Hess Kenny Girija Krishnamurthy Franklin Moy Susan Petusky Diane Tkach Nancy Torres Biqi Wu Weixin Xu 《Bioorganic & medicinal chemistry letters》2009,19(1):62-66
Insulin-like growth factor receptor (IGF-1R) is a growth factor receptor tyrosine kinase that acts as a critical mediator of cell proliferation and survival. Inhibitors of this receptor are believed to provide a new target in cancer therapy. We previously reported an isoquinolinedione series of IGF-1R inhibitors. Now we have identified a series of 3-cyanoquinoline compounds that are low nanomolar inhibitors of IGF-1R. The strategies, synthesis, and SAR behind the cyanoquinoline scaffold will be discussed. 相似文献
2.
Vasudevan A Verzal MK Villamil CI Stewart KD Abad-Zapatero C Oie T Djuric SW 《Bioorganic & medicinal chemistry letters》2012,22(14):4502-4505
The design and synthesis of indazolinone containing kinase inhibitors are reported. Regioisomers that showed profound potency variation in previously-reported isoindolinone and aminoindazole systems were surprisingly found to have similar potencies in the case of the indazolinone chemical series. An interpretation using differential hinge hydrogen bonding and tautomeric equilibrium of indazolinone ring system is supported by quantum mechanics calculations. The equipotent inhibition of a representative kinase (KDR) by regioisomeric indazolinones 4 and 5 is clear evidence that in case of the indazolinone hinge, both tautomers are equally favored, and should be considered in design of inhibitors. 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.
Design, synthesis and structure-activity relationship of a series of 3-imidazolylmethylaminophenylsulfonyltetrahydroquinolines as farnesyltransferase inhibitors are presented. A working pharmacophore of inhibiting farnesyltransferase by this series of inhibitors is proposed. 相似文献
5.
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
6.
Lavoie R Bouchain G Frechette S Woo SH Abou-Khalil E Leit S Fournel M Yan PT Trachy-Bourget MC Beaulieu C Li Z Besterman J Delorme D 《Bioorganic & medicinal chemistry letters》2001,11(21):2847-2850
Histone deacetylase inhibitors (HDACs) have emerged as a novel class of antiproliferative agents. Utilizing structure-based design, the synthesis of a series of sulfonamide hydroxamic acids is described. Further optimization of this series by substitution of the terminal aromatic ring yielded HDAC inhibitors with good in vitro and in vivo activities. 相似文献
7.
Iwanowicz EJ Watterson SH Liu C Gu HH Mitt T Leftheris K Barrish JC Fleener CA Rouleau K Sherbina NZ Hollenbaugh DL 《Bioorganic & medicinal chemistry letters》2002,12(20):2931-2934
A series of novel guanidine-based small molecule inhibitors of inosine monophosphate dehydrogenase (IMPDH) was explored. IMPDH catalyzes the rate determining step in guanine nucleotide biosynthesis and is a target for anticancer, immunosuppressive and antiviral therapy. The synthesis and the structure-activity relationships (SARs), derived from in vitro studies, for this new series of inhibitors is given. 相似文献
8.
Irvine MW Patrick GL Kewney J Hastings SF MacKenzie SJ 《Bioorganic & medicinal chemistry letters》2008,18(6):2032-2037
The discovery, synthesis and in vitro activity of a novel series of rhodanine based phosphodiesterase-4 (PDE4) inhibitors is described. Structure-activity relationship studies directed toward improving potency led to the development of submicromolar inhibitors 2n and 3i (IC(50)=0.89 & 0.74 microM). The replacement of rhodanine with structurally related heterocycles was also investigated and led to the synthesis of pseudothiohydantoin 7 (IC(50)=0.31 microM). 相似文献
9.
Dhar TG Shen Z Gu HH Chen P Norris D Watterson SH Ballentine SK Fleener CA Rouleau KA Barrish JC Townsend R Hollenbaugh DL Iwanowicz EJ 《Bioorganic & medicinal chemistry letters》2003,13(20):3557-3560
A series of novel small molecule inhibitors of inosine monophosphate dehydrogenase (IMPDH), based upon a 3-cyanoindole core, were explored. IMPDH catalyzes the rate determining step in guanine nucleotide biosynthesis and is a target for anticancer, immunosuppressive and antiviral therapy. The synthesis and the structure-activity relationships (SAR), derived from in vitro studies, for this new series of inhibitors is given. 相似文献
10.
Junqing Guo Andrew Watson James Kempson Marianne Carlsen Joseph Barbosa Karen Stebbins Deborah Lee John Dodd Steven G. Nadler Murray McKinnon Joel Barrish William J. Pitts 《Bioorganic & medicinal chemistry letters》2009,19(7):1935-1938
A series of pyrimidine based inhibitors of PDE7 are discussed. The synthesis, structure–activity relationships (SAR) and selectivity against several other PDE family members as well as activity in T cells are presented. These compounds were found to have effects on T cell proliferation, however it is not clear whether the mechanism is related to PDE7 inhibition. 相似文献
11.
John Liddle Paul Bamborough Michael D. Barker Sebastien Campos Rick P.C. Cousins Geoffrey J. Cutler Heather Hobbs Duncan S. Holmes Chris Ioannou Geoff W. Mellor Mary A. Morse Jeremy J. Payne John M. Pritchard Kathryn J. Smith Daniel T. Tape Caroline Whitworth Richard A. Williamson 《Bioorganic & medicinal chemistry letters》2009,19(9):2504-2508
The synthesis and SAR of a novel series of IKK2 inhibitors are described. Modification around the hinge binding region of the 7-azaindole led to a series of potent and selective inhibitors with good cellular activity. 相似文献
12.
Mark D. Rosen Craig R. Woods Steven D. Goldberg Michael D. Hack A. Dawn Bounds Young Yang Pamela C. Wagaman Victor K. Phuong Angela P. Ameriks Terrance D. Barrett Kimon C. Kanelakis Jui Chang Nigel P. Shankley Michael H. Rabinowitz 《Bioorganic & medicinal chemistry letters》2009,19(23):6548-6551
A series of indeno[1,2-c]pyrazoles were discovered to be the first known inhibitors of heme-regulated eukaryotic initiation factor 2α (HRI) kinase. The synthesis, structure–activity relationship profile, and in-vitro pharmacological characterization of this inaugural series of HRI kinase inhibitors are detailed. 相似文献
13.
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
14.
E Takashiro Y Nakamura S Miyamoto Y Ozawa A Sugiyama K Fujimoto 《Bioorganic & medicinal chemistry》1999,7(9):2105-2114
The synthesis and the SAR study of novel pseudo symmetric inhibitors of HIV-1 protease are described. Michael addition of amino acid derivatives to vinyl ketones was utilized to derive a potent (nM) series of HIV-1 protease inhibitors. 相似文献
15.
Benjamin E. Blass Pravin Iyer Magid Abou-Gharbia Wayne E. Childers John C. Gordon Mercy Ramanjulu George Morton Premkumar Arumugam Joshodeep Boruwa John Ellingboe Sayan Mitra Rajashekar Reddy Nimmareddy Shalini Paliwal Jamallamudi Rajasekhar Savithiri Shivakumar Pratima Srivastava Raghuram S. Tangirala Konda Venkataramanaiah L. Krishnakanth Reddy 《Bioorganic & medicinal chemistry letters》2018,28(13):2270-2274
The synthesis of steroid hormones is critical to human physiology and improper regulation of either the synthesis of these key molecules or activation of the associated receptors can lead to disease states. This has led to intense interest in developing compounds capable of modulating the synthesis of steroid hormones. Compounds capable of inhibiting Cyp19 (Aromatase), a key enzyme in the synthesis of estrogens, have been successfully employed as breast cancer therapies, while inhibitors of Cyp17 (17α-hydroxylase-17,20-lyase), a key enzyme in the synthesis of glucocorticoids, mineralocorticoids and steroidal sex hormones, are a key component of prostate cancer therapy. Inhibition of CYP17 has also been suggested as a possible target for the treatment of Cushing Syndrome and Metabolic Syndrome. We have identified two novel series of stilbene based CYP17 inhibitors and demonstrated that exemplary compounds in these series have pharmacokinetic properties consistent with orally delivered drugs. These findings suggest that compounds in these classes may be useful for the treatment of diseases and conditions associated with improper regulation of glucocorticoids synthesis and glucocorticoids receptor activation. 相似文献
16.
Potentiation of cytotoxic drug activity in human tumour cell lines, by amine-substituted 2-arylbenzimidazole-4-carboxamide PARP-1 inhibitors 总被引:3,自引:0,他引:3
White AW Curtin NJ Eastman BW Golding BT Hostomsky Z Kyle S Li J Maegley KA Skalitzky DJ Webber SE Yu XH Griffin RJ 《Bioorganic & medicinal chemistry letters》2004,14(10):2433-2437
The synthesis and biological evaluation of a new series of amine-substituted 2-arylbenzimidazole-4-carboxamide inhibitors of the DNA-repair enzyme poly(ADP-ribose) polymerase-1 (PARP-1) is reported. The introduction of an amine substituent at the 2-aryl position is not detrimental to activity, with most inhibitors exhibiting K(i) values for PARP-1 inhibition in the low nanomolar range. Two compounds in this series were found to potentiate the cytotoxicity of the DNA-methylating agent temozolomide by 4-5-fold in a human colorectal cancer cell line. 相似文献
17.
Flagellar formation in the true slime mold,Physarum polycephalum, involves a sequence of events during which amoebae are changed into flagellate cells. In the present study a series of inhibitors
thought to inhibit RNA and protein synthesis and microtubule assembly were added in an attempt to characterize the metabolic
processes associated with this amoebo-flagellate transformation.
Proflavin (inhibitor of cellular RNA synthesis), puromycin, cycloheximide and streptomycin (inhibitors of protein synthesis),
blocked the transformation; however, actinomycin D (inhibitor of DNA-dependent RNA synthesis) did not block this transformation.
On the other hand, 2-mercaptoethanol and dithiothreitol did block flagella formation, but even high concentrations of colchicine
failed to have such an effect.
Flagellate formation was more strongly inhibited by inhibitors of oxidative phosphorylation than by other respiratory inhibitors;
this suggests that oxidative phosphorylation takes part in the energy metabolism of this transformation. 相似文献
18.
Evans JM Turner BA Bowen S Ho AM Sarver RW Benson E Parker CN 《Bioorganic & medicinal chemistry letters》2003,13(6):993-996
Screening for inhibitors of bacterial protein synthesis Initiation Factor 2 (IF2) binding to N-formyl-Methionyl-transfer RNA (fMet-tRNA((fMet))) identified a series of aminoglycosides, that included amikacin and kanamycin A1, as inhibitors of this interaction. Subsequent testing revealed that aminoglycosides displayed a wide range of inhibitory activity. However, the failure of these compounds to completely inhibit binding of IF2 to fMet-tRNA((fMet)), the known ability of aminoglycosides to bind RNA, and the ability of the aminoglycosides to displace PicoGreen bound to fMet-tRNA((fMet)) suggest these compounds act by binding fMet-tRNA((fMet)). This hypothesis is further supported by isothermal denaturation experiments that failed to show any interaction between the IF2 protein and the aminoglycosides. 相似文献
19.
Christopher J. Burns Michael F. Harte Xianyong Bu Emmanuelle Fantino Marilena Giarrusso Max Joffe Margarita Kurek Fiona S. Legge Pasquale Razzino Stephen Su Herbert Treutlein Soo San Wan Jun Zeng Andrew F. Wilks 《Bioorganic & medicinal chemistry letters》2009,19(4):1206-1209
A series of 2-(α-methylbenzylamino) pyrazines have shown to be potent inhibitors of the FMS tyrosine receptor kinase. Details of SAR studies, modeling and synthesis of compounds within this series are reported. 相似文献
20.
Grimm EL Roy B Aspiotis R Bayly CI Nicholson DW Rasper DM Renaud J Roy S Tam J Tawa P Vaillancourt JP Xanthoudakis S Zamboni RJ 《Bioorganic & medicinal chemistry》2004,12(5):845-851
A robust method for the solid phase synthesis of a series of selective caspase-3 peptide inhibitors is described. The inhibitors can be obtained after cleavage from the solid support without further purification. 相似文献