共查询到20条相似文献,搜索用时 10 毫秒
1.
Takle AK Brown MJ Davies S Dean DK Francis G Gaiba A Hird AW King FD Lovell PJ Naylor A Reith AD Steadman JG Wilson DM 《Bioorganic & medicinal chemistry letters》2006,16(2):378-381
A novel triarylimidazole derivative, SB-590885 (33), bearing a 2,3-dihydro-1H-inden-1-one oxime substituent has been identified as a potent and extremely selective inhibitor of B-Raf kinase. 相似文献
2.
Xiaolun Wang Dan M. Berger Edward J. Salaski Nancy Torres Yongbo Hu Jeremy I. Levin Dennis Powell Donald Wojciechowicz Karen Collins Eileen Frommer 《Bioorganic & medicinal chemistry letters》2009,19(23):6571-6574
A series of pyrazolo[1,5-α]pyrimidine analogs has been prepared and found to be potent and selective B-Raf inhibitors. Molecular modeling suggests they bind to the active conformation of the enzyme. 相似文献
3.
Buckmelter AJ Ren L Laird ER Rast B Miknis G Wenglowsky S Schlachter S Welch M Tarlton E Grina J Lyssikatos J Brandhuber BJ Morales T Randolph N Vigers G Martinson M Callejo M 《Bioorganic & medicinal chemistry letters》2011,21(4):1248-1252
Virtual and high-throughput screening identified imidazo[1,2-a]pyrazines as inhibitors of B-Raf. We describe the rationale, SAR, and evolution of the initial hits to a series of furo[2,3-c]pyridine indanone oximes as highly potent and selective inhibitors of B-Raf. 相似文献
4.
The identification of potent, selective and CNS penetrant furan-based inhibitors of B-Raf kinase 总被引:1,自引:0,他引:1
Takle AK Bamford MJ Davies S Davis RP Dean DK Gaiba A Irving EA King FD Naylor A Parr CA Ray AM Reith AD Smith BB Staton PC Steadman JG Stean TO Wilson DM 《Bioorganic & medicinal chemistry letters》2008,18(15):4373-4376
Modification of the potent imidazole-based B-Raf inhibitor SB-590885 resulted in the identification of a series of furan-based derivatives with enhanced CNS penetration. One such compound, SB-699393 (17), was examined in vivo to challenge the hypothesis that selective B-Raf inhibitors may be of value in the treatment of stroke. 相似文献
5.
Hansen JD Grina J Newhouse B Welch M Topalov G Littman N Callejo M Gloor S Martinson M Laird E Brandhuber BJ Vigers G Morales T Woessner R Randolph N Lyssikatos J Olivero A 《Bioorganic & medicinal chemistry letters》2008,18(16):4692-4695
Herein we describe a novel pyrazole-based class of ATP competitive B-Raf inhibitors. These inhibitors exhibit both excellent cellular potency and striking B-Raf selectivity. A subset of these inhibitors has demonstrated the ability to inhibit downstream ERK phosphorylation in LOX tumors from mouse xenograft studies. 相似文献
6.
Dan M. Berger Nancy Torres Minu Dutia Dennis Powell Greg Ciszewski Ariamala Gopalsamy Jeremy I. Levin Kyung-Hee Kim Weixin Xu James Wilhelm YongBo Hu Karen Collins Larry Feldberg Steven Kim Eileen Frommer Donald Wojciechowicz Robert Mallon 《Bioorganic & medicinal chemistry letters》2009,19(23):6519-6523
As part of our research effort to discover B-Raf kinase inhibitors, we prepared a series of C-3 substituted N-(3-(pyrazolo[1,5-a]pyrimidin-7-yl)phenyl)-3-(trifluoromethyl)benzamides. X-ray crystallography studies revealed that one of the more potent inhibitors (10n) bound to B-Raf kinase without forming a hinge-binding hydrogen bond. With basic amine residues appended to C-3 aryl residues, cellular activity and solubility were enhanced over previously described compounds of this class. 相似文献
7.
Martin J. Di Grandi Dan M. Berger Darrin W. Hopper Chunchun Zhang Minu Dutia Alejandro L. Dunnick Nancy Torres Jeremy I. Levin George Diamantidis Christoph W. Zapf Jonathan D. Bloom YongBo Hu Dennis Powell Donald Wojciechowicz Karen Collins Eileen Frommer 《Bioorganic & medicinal chemistry letters》2009,19(24):6957-6961
A novel series of pyrazolo[1,5-a]pyrimidines bearing a 3-hydroxyphenyl group at C(3) and substituted tropanes at C(7) have been identified as potent B-Raf inhibitors. Exploration of alternative functional groups as a replacement for the C(3) phenol demonstrated indazole to be an effective isostere. Several compounds possessing substituted indazole residues, such as 4e, 4p, and 4r, potently inhibited cell proliferation at submicromolar concentrations in the A375 and WM266 cell lines, and the latter two compounds also exhibited good therapeutic indices in cells. 相似文献
8.
The discovery of potent cRaf1 kinase inhibitors 总被引:8,自引:0,他引:8
Lackey K Cory M Davis R Frye SV Harris PA Hunter RN Jung DK McDonald OB McNutt RW Peel MR Rutkowske RD Veal JM Wood ER 《Bioorganic & medicinal chemistry letters》2000,10(3):223-226
A series of benzylidene-1H-indol-2-one (oxindole) derivatives was synthesized and evaluated as cRaf-1 kinase inhibitors. The key features of the molecules were the donor/acceptor motif common to kinase inhibitors and a critical acidic phenol flanked by two substitutions. Diverse 5-position substitutions provided compounds with low nanomolar kinase enzyme inhibition and inhibited the intracellular MAPK pathway. 相似文献
9.
Renee Aspiotis Denis Deschênes Daniel Dubé Yves Girard Zheng Huang France Laliberté Susana Liu Robert Papp Donald W. Nicholson Robert N. Young 《Bioorganic & medicinal chemistry letters》2010,20(18):5502-5505
The SAR study of a series of 6-aryloxymethyl-8-aryl substituted quinolines is described. Optimization of the series led to the discovery of compound 26b, a highly potent (IC50 = 0.6 nM) and selective PDE4D inhibitor with a 75-fold selectivity over the A, B, and C subtypes and over 18,000-fold selectivity against other PDE family members. Rat pharmacokinetics and tissue distribution are also summarized. 相似文献
10.
Hamblett CL Methot JL Mampreian DM Sloman DL Stanton MG Kral AM Fleming JC Cruz JC Chenard M Ozerova N Hitz AM Wang H Deshmukh SV Nazef N Harsch A Hughes B Dahlberg WK Szewczak AA Middleton RE Mosley RT Secrist JP Miller TA 《Bioorganic & medicinal chemistry letters》2007,17(19):5300-5309
This communication highlights the development of a nicotinamide series of histone deacetylase inhibitors within the benzamide structural class. Extensive exploration around the nicotinamide core led to the discovery of a class I selective HDAC inhibitor that possesses excellent intrinsic and cell-based potency, acceptable ancillary pharmacology, favorable pharmacokinetics, sustained pharmacodynamics in vitro, and achieves in vivo efficacy in an HCT116 xenograft model. 相似文献
11.
Graham Robinett R Freemerman AJ Skinner MA Shewchuk L Lackey K 《Bioorganic & medicinal chemistry letters》2007,17(21):5886-5893
Substituted 4-(3-hydroxyanilino)-quinoline compounds, initially identified as small-molecule inhibitors of src family kinases, have been evaluated as potential inhibitors of RET kinase. Three compounds, 38, 31, and 40, had K(i)'s of 3, 25, and 50 nM in an in vitro kinase assay; while a cell based kinase assay showed K(i)'s of 300, 100, and 45 nM, respectively. These compounds represent potential new leads for the treatment of medullary and papillary thyroid cancer. 相似文献
12.
KK Liu S Bailey DM Dinh H Lam C Li PA Wells MJ Yin A Zou 《Bioorganic & medicinal chemistry letters》2012,22(15):5114-5117
Novel conformationally-restricted mTOR kinase inhibitors with cyclic sulfone scaffold were designed. Synthesis and structure-activity relationship (SAR) studies are described with emphasis on optimization of the mTOR potency and selectivity against class I PI3Kα kinase. PF-05139962 was identified with excellent mTOR biochemical inhibition, cellular potency, kinase selectivity and in vitro ADME properties. 相似文献
13.
Ren L Ahrendt KA Grina J Laird ER Buckmelter AJ Hansen JD Newhouse B Moreno D Wenglowsky S Dinkel V Gloor SL Hastings G Rana S Rasor K Risom T Sturgis HL Voegtli WC Mathieu S 《Bioorganic & medicinal chemistry letters》2012,22(10):3387-3391
Herein we describe the discovery of a novel series of ATP competitive B-Raf inhibitors via structure based drug design (SBDD). These pyridopyrimidin-7-one based inhibitors exhibit both excellent cellular potency and striking B-Raf selectivity. Optimization led to the identification of compound 17, a potent, selective and orally available agent with excellent pharmacokinetic properties and robust tumor growth inhibition in xenograft studies. 相似文献
14.
Côté B Frenette R Prescott S Blouin M Brideau C Ducharme Y Friesen RW Laliberté F Masson P Styhler A Girard Y 《Bioorganic & medicinal chemistry letters》2003,13(4):741-744
The synthesis and the biological evaluation of new potent phosphodiesterase type 4 (PDE4) inhibitors are presented. This new series was elaborated by replacement of the metabolically resistant phenyl hexafluorocarbinol of L-791,943 (1) by a substituted aminopyridine residue. The structure-activity relationship of N-substitution on 3 led to the identification of (-)-3n which exhibited a good PDE4 inhibitor activity (HWB-TNFalpha=0.12 microM) and an improved pharmacokinetic profile over L-791,943 (rat t(1/2)=2 h). (-)-3n was well tolerated in ferret with an emetic threshold of 30 mg/kg (po) and was found to be active in the ovalbumin-induced bronchoconstriction model in guinea pig (54%, 0.1 mg/kg, ip) as well as the ascaris-induced bronchoconstriction model in sheep (64%/97%, early/late, 0.5 mg/kg, iv). 相似文献
15.
Karine Malagu Heather Duggan Keith Menear Marc Hummersone Sylvie Gomez Christine Bailey Peter Edwards Jan Drzewiecki Frédéric Leroux Mar Jimenez Quesada Gesine Hermann Stephanie Maine Carrie-Anne Molyneaux Armelle Le Gall James Pullen Ian Hickson Lisa Smith Sharon Maguire Niall Martin Graeme Smith Martin Pass 《Bioorganic & medicinal chemistry letters》2009,19(20):5950-5953
We describe a novel series of potent inhibitors of the kinase activity of mTOR. The compounds display good selectivity relative to other PI3K-related kinase family members and, in cellular assays, inhibit both mTORC1 and mTORC2 complexes and exhibit good antiproliferative activity. 相似文献
16.
Tang J Hamajima T Nakano M Sato H Dickerson SH Lackey KE 《Bioorganic & medicinal chemistry letters》2008,18(16):4610-4614
The synthesis of a 7-azaindole series of novel, potent B-Raf kinase inhibitors using knowledge-based design was carried out. Compound 6h exhibits not only excellent potency in both the enzyme assay (IC(50)=2.5 nM) and the cellular assay (IC(50)=63 nM), but also has an outstanding selectivity profile against other kinases. 相似文献
17.
David A. Scott Carrie L. Balliet Donald J. Cook Audrey M. Davies Thomas W. Gero Charles A. Omer Srinivasu Poondru Maria-Elena Theoclitou Boris Tyurin Michael J. Zinda 《Bioorganic & medicinal chemistry letters》2009,19(3):697-700
3-Amido-4-anilinoquinolines are potent and highly selective inhibitors of CSF-1R. Their synthesis and SAR is reported, along with initial efforts to optimize the physical properties and PK through modifications at the quinoline 6- and 7-positions. 相似文献
18.
Y Bi P Stoy L Adam B He J Krupinski D Normandin R Pongrac L Seliger A Watson J E Macor 《Bioorganic & medicinal chemistry letters》2001,11(18):2461-2464
The design and synthesis of a novel scaffold for potent and selective PDE5 inhibitors are described. Compound 3a was more potent (PDE5 IC50=0.31 nM) and selective (>10,000-fold vs PDE1 and 160-fold selective vs PDE6) PDE5 inhibitor than sildenafil. 相似文献
19.
Yoshiyuki Sato Yu Onozaki Tetsuya Sugimoto Hideki Kurihara Kaori Kamijo Chie Kadowaki Toshiaki Tsujino Akiko Watanabe Sachie Otsuki Morihiro Mitsuya Masato Iida Kyosuke Haze Takumitsu Machida Yoko Nakatsuru Hideya Komatani Hidehito Kotani Yoshikazu Iwasawa 《Bioorganic & medicinal chemistry letters》2009,19(16):4673-4678
A novel class of imidazopyridine derivatives was designed as PLK1 inhibitors. Extensive SAR studies supported by molecular modeling afforded a highly potent and selective compound 36. Compound 36 demonstrated good antitumor efficacy in xenograft nude rat model. 相似文献
20.
Chen S Chen L Le NT Zhao C Sidduri A Lou JP Michoud C Portland L Jackson N Liu JJ Konzelmann F Chi F Tovar C Xiang Q Chen Y Wen Y Vassilev LT 《Bioorganic & medicinal chemistry letters》2007,17(8):2134-2138
A novel series of quinolinyl-methylene-thiazolinones has been identified as potent and selective cyclin-dependent kinase 1 (CDK1) inhibitors. Their synthesis and structure activity relationships (SAR) are described. Representative compounds from this class reversibly inhibit CDK1 activity in vitro, and block cell cycle progression in human tumor cell lines, suggesting a potential use as antitumor agents. 相似文献