共查询到20条相似文献,搜索用时 0 毫秒
1.
Miyazaki Y Maeda Y Sato H Nakano M Mellor GW 《Bioorganic & medicinal chemistry letters》2008,18(6):1967-1971
4-Amino-5,6-diaryl-furo[2,3-d]pyrimidines have been identified as inhibitors of glycogen synthase kinase-3beta (GSK-3beta). One representative derivative, 4-amino-3-(4-(benzenesulfonylamino)-phenyl)-2-(3-pyridyl)-furo[2,3-d]pyrimidine (12) exhibited potent GSK-3beta inhibitory activity in low nanomolar level of IC(50). The binding mode was proposed from a docking study. 相似文献
2.
Witherington J Bordas V Gaiba A Naylor A Rawlings AD Slingsby BP Smith DG Takle AK Ward RW 《Bioorganic & medicinal chemistry letters》2003,13(18):3059-3062
A series of 6-heteroaryl-pyrazolo[3,4-b]pyridines has been optimised to afford potent inhibitors of Glycogen Synthase Kinase-3 (GSK-3). These analogues display excellent selectivity over the closely related Cyclin Dependent Kinase-2 (CDK-2). 相似文献
3.
William Kemnitzer Nilantha Sirisoma Chris May Ben Tseng John Drewe Sui Xiong Cai 《Bioorganic & medicinal chemistry letters》2009,19(13):3536-3540
We report the discovery of N-((benzo[d][1,3]dioxol-5-yl)methyl)-6-phenylthieno[3,2-d]pyrimidin-4-amine (2a) as an apoptosis inducer using our proprietary cell- and caspase-based ASAP HTS assay, and SAR study of HTS hit 2a which led to the discovery of 4-anilino-N-methylthieno[3,2-d]pyrimidines and 4-anilino-N-methylthieno[2,3-d]pyrimidines as potent apoptosis inducers. Compounds 5d and 5e were the most potent with EC50 values of 0.008 and 0.004 μM in T47D human breast cancer cells, respectively. Compound 5d was found to be highly active in the MX-1 breast cancer model. Functionally, compounds 5d and 5e both induced apoptosis through inhibition of tubulin polymerization. 相似文献
4.
Witherington J Bordas V Gaiba A Garton NS Naylor A Rawlings AD Slingsby BP Smith DG Takle AK Ward RW 《Bioorganic & medicinal chemistry letters》2003,13(18):3055-3057
A novel series of 6-aryl-pyrazolo[3,4-b]pyridines has been identified that are potent inhibitors of glycogen synthase kinase-3 (GSK-3). 相似文献
5.
Smith DG Buffet M Fenwick AE Haigh D Ife RJ Saunders M Slingsby BP Stacey R Ward RW 《Bioorganic & medicinal chemistry letters》2001,11(5):635-639
Potent 3-anilino-4-arylmaleimide glycogen synthase kinase-3 (GSK-3) inhibitors have been prepared using automated array methodology. A number of these are highly selective, having little inhibitory potency against more than 20 other protein kinases. 相似文献
6.
Vidya P. Kumar Kathleen M. Frey Yiqiang Wang Hitesh K. Jain Aleem Gangjee Karen S. Anderson 《Bioorganic & medicinal chemistry letters》2013,23(19):5426-5428
Cryptosporidiosis, a gastrointestinal disease caused by a protozoan Cryptosporidium hominis is often fatal in immunocompromised individuals. There is little clinical data to show that the existing treatment by nitazoxanide and paromomycin is effective in immunocompromised individuals.1, 2 Thymidylate synthase (TS) and dihydrofolate reductase (DHFR) are essential enzymes in the folate biosynthesis pathway and are well established as drug targets in cancer and malaria. A novel series of classical antifolates, 2-amino-4-oxo-5-substituted pyrrolo[2,3-d]pyrimidines have been evaluated as Cryptosporidium hominis thymidylate synthase (ChTS) inhibitors. Crystal structure in complex with the most potent compound, a 2′-chlorophenyl with a sulfur bridge with a Ki of 8.83 ± 0.67 nM is discussed in terms of several Van der Waals, hydrophobic and hydrogen bond interactions with the protein residues and the substrate analog 5-fluorodeoxyuridine monophosphate. Of these interactions, two interactions with the non-conserved residues (A287 and S290) offer an opportunity to develop ChTS specific inhibitors. Compound 6 serves as a lead compound for analog design and its crystal structure provides clues for the design of ChTS specific inhibitors. 相似文献
7.
Yasuko Koda Ko Kikuzato Junko Mikuni Akiko Tanaka Hitomi Yuki Teruki Honma Yuri Tomabechi Mutsuko Kukimoto-Niino Mikako Shirouzu Fumiyuki Shirai Hiroo Koyama 《Bioorganic & medicinal chemistry letters》2017,27(22):4994-4998
A series of novel pyrrolo[2,3-d]pyrimidines were synthesized by introducing 15 different amino acids to 7-cyclohexyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine. Compounds with potent activities against HCK and FLT3-ITD were evaluated in viability studies with acute myeloid leukemia cell line MV4-11. Our structure activity relationship analyses lead to the identification of compound 31, which exhibited potent HCK and FLT3-ITD inhibition and activity against the MV4-11 cell line. 相似文献
8.
Burchat AF Calderwood DJ Hirst GC Holman NJ Johnston DN Munschauer R Rafferty P Tometzki GB 《Bioorganic & medicinal chemistry letters》2000,10(19):2171-2174
Pyrrolo[2,3-d]pyrimidines containing a 5-(4-phenoxyphenyl) substituent are novel, potent and selective inhibitors of lck in vitro. Exploration of C-6 position of the pyrrolo[2,3-d]pyrimidine and the terminal phenyl group structure-activity relationship (SAR) is detailed. Compound 1 is orally active in animal models. 相似文献
9.
Arnold LD Calderwood DJ Dixon RW Johnston DN Kamens JS Munschauer R Rafferty P Ratnofsky SE 《Bioorganic & medicinal chemistry letters》2000,10(19):2167-2170
Pyrrolo[2,3-d]pyrimidines containing a 5-(4-phenoxyphenyl) substituent are potent and selective inhibitors of Ick in vitro; some compounds are selective for lck over src. Data are shown for two compounds demonstrating that they are potent and selective inhibitors of IL2 production in cells. 相似文献
10.
Witherington J Bordas V Haigh D Hickey DM Ife RJ Rawlings AD Slingsby BP Smith DG Ward RW 《Bioorganic & medicinal chemistry letters》2003,13(9):1581-1584
Introduction of a nitrogen atom into the 6-position of a series of pyrazolo[3,4-b]pyridines led to a dramatic improvement in the potency of GSK-3 inhibition. Rationalisation of the binding mode suggested participation of a putative structural water molecule, which was subsequently confirmed by X-ray crystallography. 相似文献
11.
Witherington J Bordas V Garland SL Hickey DM Ife RJ Liddle J Saunders M Smith DG Ward RW 《Bioorganic & medicinal chemistry letters》2003,13(9):1577-1580
A novel series of pyrazolo[3,4-b]pyridines has been identified that are potent inhibitors of glycogen synthase kinase-3 (GSK-3). 相似文献
12.
Maria P. Giovannoni Nicoletta Cesari Alessia Graziano Claudia Vergelli Claudio Biancalani Pierfrancesco Biagini 《Journal of enzyme inhibition and medicinal chemistry》2013,28(3):309-318
A series of pyrrolo[2,3-d]pyridazinones was synthesized and tested for their inhibitory activity on PDE4 subtypes A, B and D and selectivity toward Rolipram high affinity binding site (HARBS). New agents with interesting profile were reported; in particular compound 9e showed a good PDE4 subtype selectivity, being 8 times more potent (IC50 = 0.32 μM) for PDE4B (anti-inflammatory) than for PDE4D (IC50 = 2.5 μM), generally considered the subtype responsible for emesis. Moreover the ratio HARBS/PDE4B was particularly favourable for 9e (147), suggesting that the best arranged groups around the pyrrolopyridazinone core are an isopropyl at position-1, an ethoxycarbonyl at position-2, together with an ethyl group at position-6.For compounds 8 and 15a the ability to inhibit TNFα production in PBMC was evaluated and the results are consistent with their PDE4 inhibitory activity. 相似文献
13.
Giovannoni MP Cesari N Graziano A Vergelli C Biancalani C Biagini P Dal Piaz V 《Journal of enzyme inhibition and medicinal chemistry》2007,22(3):309-318
A series of pyrrolo [2,3-d]pyridazinones was synthesized and tested for their inhibitory activity on PDE4 subtypes A, B and D and selectivity toward Rolipram high affinity binding site (HARBS). New agents with interesting profile were reported; in particular compound 9e showed a good PDE4 subtype selectivity, being 8 times more potent (IC50 = 0.32 microM) for PDE4B (anti-inflammatory) than for PDE4D (IC50 = 2.5 microM), generally considered the subtype responsible for emesis. Moreover the ratio HARBS/PDE4B was particularly favourable for 9e (147), suggesting that the best arranged groups around the pyrrolopyridazinone core are an isopropyl at position-1, an ethoxycarbonyl at position-2, together with an ethyl group at position-6. For compounds 8 and 15a the ability to inhibit TNFalpha production in PBMC was evaluated and the results are consistent with their PDE4 inhibitory activity. 相似文献
14.
Zhang HC Ye H Conway BR Derian CK Addo MF Kuo GH Hecker LR Croll DR Li J Westover L Xu JZ Look R Demarest KT Andrade-Gordon P Damiano BP Maryanoff BE 《Bioorganic & medicinal chemistry letters》2004,14(12):3245-3250
A novel series of acyclic 3-(7-azaindolyl)-4-(aryl/heteroaryl)maleimides was synthesized and evaluated for activity against GSK-3beta and selectivity versus PKC-betaII, as well as a broad panel of protein kinases. Compounds 14 and 17c potently inhibited GSK-3beta (IC(50)=7 and 26 nM, respectively) and exhibited excellent selectivity over PKC-betaII (325 and >385-fold, respectively). Compound 17c was also highly selective against 68 other protein kinases. In a cell-based functional assay, both 14 and 17c effectively increased glycogen synthase activity by inhibiting GSK-3beta. 相似文献
15.
Calderwood DJ Johnston DN Munschauer R Rafferty P 《Bioorganic & medicinal chemistry letters》2002,12(12):1683-1686
A series of pyrrolo[2,3-d]pyrimidines was synthesized and evaluated as inhibitors of Lck. Lck accommodates a diverse set of substituents at N-7. Altering the substituent at N-7 provided compound 13, an orally available lck inhibitor which inhibited TCR mediated IL-2 production after oral dosing. 相似文献
16.
A series of 17 novel 2-amino-4-oxo-5-[(substituted phenyl)thio]pyrrolo[2,3-d]pyrimidines were synthesized as potential inhibitors of thymidylate synthase (TS) and as antitumor agents. The analogues contain a variety of electron withdrawing substituents on the phenyl ring of the side chain and were evaluated as inhibitors of human TS (hTS) and Escherichia coli TS and of human and E. coli dihydrofolate reductase (DHFR). The analogues 14, 17, and 18 were potent inhibitors of hTS with IC50 values of 0.28, 0.21, and 0.22 microM, respectively, and were more potent than the clinically used ZD1694, 2 and LY231514, 3 against human TS. 相似文献
17.
Shigehiro Asano Masafumi Komiya Nobuyuki Koike Erina Koga Shogo Nakatani Yoshiaki Isobe 《Bioorganic & medicinal chemistry letters》2010,20(22):6696-6698
A novel series of 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidines containing substituted phenyl sulfonamide are synthesized and evaluated for their inhibitory activity against CaMKII. Substituents on the phenyl group had significant impact on CaMKII inhibition, in particular, the inhibitory activity of 8p was 25-fold higher than that of KN-93, a known CaMKII inhibitor. Michaelis–Menten analysis of a representative compound suggested that the synthesized pyrimidines are calmodulin non-competitive inhibitors. Finally, 8p exhibited more than 100-fold higher selectivity for CaMKII over five types of off-target kinases. 相似文献
18.
Sleebs BE Nikolakopoulos G Street IP Falk H Baell JB 《Bioorganic & medicinal chemistry letters》2011,21(19):5992-5994
4-Aminobenzothieno[3,2-d]pyrimidines were previously identified in a high throughput screening campaign as LIMK1 inhibitors. Scaffold reversal led to the identification of a series of simple 5,6-substituted 4-aminothieno[2,3-d]pyrimidines with low micromolar inhibition of LIMK1. 相似文献
19.
Miyazaki Y Matsunaga S Tang J Maeda Y Nakano M Philippe RJ Shibahara M Liu W Sato H Wang L Nolte RT 《Bioorganic & medicinal chemistry letters》2005,15(9):2203-2207
A novel class of furo[2,3-d]pyrimidines has been discovered as potent dual inhibitors of Tie-2 and VEGFR2 receptor tyrosine kinases (TK) and a diarylurea moiety at 5-position shows remarkably enhanced activity against both enzymes. One of the most active compounds, 4-amino-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)amino-carbonylamino)phenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine (7k) is <3 nM on both TK receptors and the activity is rationalized based on the X-ray crystal structure. 相似文献
20.
Packard GK Papa P Riggs JR Erdman P Tehrani L Robinson D Harris R Shevlin G Perrin-Ninkovic S Hilgraf R McCarrick MA Tran T Fleming Y Bai A Richardson S Katz J Tang Y Leisten J Moghaddam M Cathers B Zhu D Sakata S 《Bioorganic & medicinal chemistry letters》2012,22(1):747-752
The serine/threonine specific protein kinase B-Raf is part of the MAPK pathway and is an interesting oncology target. We have identified thieno[2,3-d]pyrimidines as a core scaffold of small molecule B-Raf inhibitors. The SAR of analogs in this series will be described. 相似文献