共查询到20条相似文献,搜索用时 0 毫秒
1.
Farmer LJ Bemis G Britt SD Cochran J Connors M Harrington EM Hoock T Markland W Nanthakumar S Taslimi P Ter Haar E Wang J Zhaveri D Salituro FG 《Bioorganic & medicinal chemistry letters》2008,18(23):6231-6235
A series of SYK inhibitors based on the phenylamino pyrimidine thiazole lead 4 were prepared and evaluated for biological activity. Lead optimization provided compounds with nanomolar K(i)'s against SYK and potent inhibition in mast cell degranulation assays. 相似文献
2.
Radi M Crespan E Botta G Falchi F Maga G Manetti F Corradi V Mancini M Santucci MA Schenone S Botta M 《Bioorganic & medicinal chemistry letters》2008,18(3):1207-1211
A series of substituted benzoylamino-2-[(4-benzyl)thio]-1,3,4-thiadiazoles has been discovered as potent Abl tyrosine kinase inhibitors. Molecular docking simulations on the Abl tyrosine kinase were conducted in order to rationalize the SAR of the synthesized inhibitors. The most active compound identified from the enzymatic screening (6a) showed interesting inhibitory activity on Imatinib-sensitive murine myeloid 3B clone and Bcr-Abl-independent Imatinib-resistant leukemia cells. Surprisingly, 6a was also proved to act as differentiating inducers in human promyelocytic leukemia cells (HL-60). 相似文献
3.
《Bioorganic & medicinal chemistry letters》2014,24(1):161-164
The design and synthesis of isoxazole 3 is described, a potent JNK inhibitor with two fold selectivity over p38. Optimization of this scaffold led to compounds 27 and 28 which showed greatly improved selectivity over p38 by maintaining the JNK3 potency of compound 3. Extensive SAR studies will be described as well as preliminary in vivo data of the two lead compounds. 相似文献
4.
Discovery and SAR of novel,potent and selective protein tyrosine phosphatase 1B inhibitors 总被引:2,自引:0,他引:2
Pei Z Li X Liu G Abad-Zapatero C Lubben T Zhang T Ballaron SJ Hutchins CW Trevillyan JM Jirousek MR 《Bioorganic & medicinal chemistry letters》2003,13(19):3129-3132
A salicylate second site binder was linked to three classes of phosphotyrosine mimetics to produce potent protein tyrosine phosphatase 1B (PTP1B) inhibitors which exhibit significant selectivity against other phosphatases including the most homologous member, TCPTP. 相似文献
5.
He Y Kamenecka TM Shin Y Song X Jiang R Noel R Duckett D Chen W Ling YY Cameron MD Lin L Khan S Koenig M LoGrasso PV 《Bioorganic & medicinal chemistry letters》2011,21(6):1719-1723
Quinazoline 3 was discovered as a novel c-jun N-terminal kinase (JNK) inhibitor with good brain penetration and pharmacokinetic (PK) properties. A number of analogs which were potent both in the biochemical and cellular assays were discovered. Quinazoline 13a was found to be a potent JNK3 inhibitor (IC50 = 40 nM), with >500-fold selectivity over p38, and had good PK and brain penetration properties. With these properties, 13a is considered a potential candidate for in vivo evaluation. 相似文献
6.
Sammond DM Nailor KE Veal JM Nolte RT Wang L Knick VB Rudolph SK Truesdale AT Nartey EN Stafford JA Kumar R Cheung M 《Bioorganic & medicinal chemistry letters》2005,15(15):3519-3523
A series of dianilinopyrimidineureas demonstrate potency as VEGFR2 kinase inhibitors. 相似文献
7.
Lai JY Cox PJ Patel R Sadiq S Aldous DJ Thurairatnam S Smith K Wheeler D Jagpal S Parveen S Fenton G Harrison TK McCarthy C Bamborough P 《Bioorganic & medicinal chemistry letters》2003,13(18):3111-3114
A series of oxindoles demonstrating inhibition of the phosphorylation of biotinylated substrates of Syk and IgE/Fc epsilon RI triggered basophil cell degranulation has been identified. A study of the SAR around sulfonamide 31 (IC(50)=5 nM, EC(50)=1400 nM) is discussed. The modest cellular activity representative of the sulfonamide series was overcome when the Polar Surface Area was lowered to <110 A(2), leading to the identification of amide 32 (IC(50)=145 nM, EC(50)=100 nM). 相似文献
8.
Chih-Hung Chen On Lee Chung-Niang Yao Meng-Yun Chuang Yow-Lone Chang May-Hua Chang Yen-Fang Wen Wan-Hsu Yang Ching-Huai Ko Nien-Tzu Chou Mai-Wei Lin Chin-Pen Lai Chung-Yuan Sun Ling-mei Wang Yen-Chun Chen Tzong-Hsiung Hseu Chia-Ni Chang Hui-Chun Hsu Hui-Chi Lin Yu-Li Chang Chrong-Shiong Hwang 《Bioorganic & medicinal chemistry letters》2010,20(20):6129-6132
A series of azulene-based derivatives were synthesized as potent inhibitors for receptor tyrosine kinases such as FMS-like tyrosine kinase 3 (FLT-3). Systematic side chain modification of prototype 1a was carried out through SAR studies. Analogue 22 was identified from this series and found to be one of the most potent FLT-3 inhibitors, with good pharmaceutical properties, superior efficacy, and tolerability in a tumor xenograft model. 相似文献
9.
Basu S Prasad UV Barawkar DA De S Palle VP Menon S Patel M Thorat S Singh UP Das Sarma K Waman Y Niranjan S Pathade V Gaur A Reddy S Ansari S 《Bioorganic & medicinal chemistry letters》2012,22(8):2843-2849
A series of novel heterocyclic carboxylic acid based protein tyrosine phosphatase 1B (PTP1B) inhibitors with hydrophobic tail have been synthesized and characterized. Structure-activity relationship (SAR) optimization resulted in identification of several potent, selective (over the highly homologous T-cell protein tyrosine phosphatase, TCPTP) and metabolically stable PTP1B inhibitors. Compounds 7a, 19a and 19c showed favorable cell permeability and pharmacokinetic properties in mouse with moderate to very good oral (% F=13-70) bio-availability. 相似文献
10.
Mahmoud S. Abdelbaset Mohamed Abdel-Aziz Mohamed Ramadan Mostafa H. Abdelrahman Syed Nasir Abbas Bukhari Taha F.S. Ali Gamal El-Din A. Abuo-Rahma 《Bioorganic & medicinal chemistry》2019,27(6):1076-1086
Novel thienoquinoline carboxamide-chalcone derivatives were prepared via the cyclization of acylated chalcones and 2-mercaptoquinoline-3-carbaldehyde in DMF with K2CO3. Thienoquinolines 9a–f, h exhibited promising antiproliferative effect against all the tested cell lines and gave a significant activity as EGFR inhibitors, with IC50 values ranging from 0.5 and 3.2?µM, and compounds 9e and 9f being the most active of the series. They also showed better activity than Erlotinib against melanoma cancer cell line A375. Moreover, compound 9f influenced pre G1 apoptosis and cell cycle arrest at G2/M phase. The binding mode of the best EGFR inhibitor 9e in the EGFR active site revealed that the thienoquinoline ring occupied the ATP-binding site while the chalcone moiety is located in the allosteric site and is responsible for the enhanced activity of these compounds. 相似文献
11.
Alam M Beevers RE Ceska T Davenport RJ Dickson KM Fortunato M Gowers L Haughan AF James LA Jones MW Kinsella N Lowe C Meissner JW Nicolas AL Perry BG Phillips DJ Pitt WR Platt A Ratcliffe AJ Sharpe A Tait LJ 《Bioorganic & medicinal chemistry letters》2007,17(12):3463-3467
The development of a series of novel aminopyrimidines as inhibitors of c-Jun N-terminal kinases is described. The synthesis, in vitro inhibitory values for JNK1, JNK2 and CDK2, and the in vitro inhibitory value for a c-Jun cellular assay are discussed. 相似文献
12.
By using of structure-based virtual screening, 13 novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors were discovered from 197,116 compounds in the SPECS database here. Among them, 8 compounds significantly inhibited EGFR kinase activity with IC(50) values lower than 10 μM. 3-{[1-(3-Chloro-4-fluorophenyl)-3,5-dioxo-4-pyrazolidinylidene]methyl}phenyl 2-thiophenecarboxylate (13), particularly, was the most potent inhibitor possessing the IC(50) value of 3.5 μM. The docking studies also provide some useful information that the docking models of the 13 compounds are beneficial to find a new path for designing novel EGFR inhibitors. 相似文献
13.
Das J Furch JA Liu C Moquin RV Lin J Spergel SH McIntyre KW Shuster DJ O'Day KD Penhallow B Hung CY Doweyko AM Kamath A Zhang H Marathe P Kanner SB Lin TA Dodd JH Barrish JC Wityak J 《Bioorganic & medicinal chemistry letters》2006,16(14):3706-3712
A series of structurally novel aminothiazole based small molecule inhibitors of Itk were prepared to elucidate their structure-activity relationships (SARs), selectivity, and cell activity in inhibiting IL-2 secretion in a Jurkat T-cell assay. Compound 3 is identified as a potent and selective Itk inhibitor which inhibits anti-TCR antibody induced IL-2 production in mice in vivo and was previously reported to reduce lung inflammation in a mouse model of ovalbumin induced allergy/asthma. 相似文献
14.
《Bioorganic & medicinal chemistry letters》2020,30(4):126930
Glycogen synthase kinase-3 plays an essential role in multiple biochemical pathways in the cell, particularly in regards to energy regulation. As such, Glycogen synthase kinase-3 is an attractive target for pharmacological intervention in a variety of disease states, particularly non-insulin dependent diabetes mellitus. However, due to homology with other crucial kinases, such as the cyclin-dependent protein kinase CDC2, developing compounds that are both potent and selective is challenging. A novel series of derivatives of 5-nitro-N2-(2-(pyridine-2ylamino)ethyl)pyridine-2,6-diamine were synthesized and have been shown to potently inhibit glycogen synthase kinase-3 (GSK3). Potency in the low nanomolar range was obtained along with remarkable selectivity. The compounds activate glycogen synthase in insulin receptor-expressing CHO-IR cells and in primary rat hepatocytes, and have acceptable pharmacokinetics and pharmacodynamics to allow for oral dosing. The X-ray co-crystal structure of human GSK3-β in complex with compound 2 is reported and provides insights into the structural determinants of the series responsible for its potency and selectivity. 相似文献
15.
Caterina Torrisi Monica Bisbocci Raffaele Ingenito Jesus M. Ontoria Michael Rowley Carsten Schultz-Fademrecht Carlo Toniatti Philip Jones 《Bioorganic & medicinal chemistry letters》2010,20(2):448-452
A novel hexahydrobenzonaphthyridinone PARP-1 pharmacophore is reported, subsequent SAR exploration around this scaffold led to selective PARP-1 inhibitors with low nanomolar enzyme potency, displaying good cellular activity and promising rat PK properties. 相似文献
16.
Dmitry O. Koltun Eric Q. Parkhill Rao Kalla Thao D. Perry Elfatih Elzein Xiaofen Li Scott P. Simonovich Christopher Ziebenhaus Timothy R. Hansen Bruno Marchand WaiLok K. Hung Leanna Lagpacan Magdeleine Hung Ron G. Aoyama Bernard P. Murray Jason K. Perry John R. Somoza Armando G. Villaseñor Jeff A. Zablocki 《Bioorganic & medicinal chemistry letters》2018,28(3):541-546
We hereby disclose the discovery of inhibitors of CaMKII (7h and 7i) that are highly potent in rat ventricular myocytes, selective against hERG and other off-target kinases, while possessing good CaMKII tissue isoform selectivity (cardiac γ/δ vs. neuronal α/β). In vitro and in vivo ADME/PK studies demonstrated the suitability of these CaMKII inhibitors for PO (7h rat F?=?73%) and IV pharmacological studies. 相似文献
17.
Matthew W. Martin David R. Lancia Hongbin Li Shawn E.R. Schiller Angela V. Toms Zhongguo Wang Kenneth W. Bair Jennifer Castro Shawn Fessler Deepali Gotur Stephen E. Hubbs Goss S. Kauffman Mark Kershaw George P. Luke Crystal McKinnon Lili Yao Wei Lu David S. Millan 《Bioorganic & medicinal chemistry letters》2019,29(8):1001-1006
The discovery, structure-activity relationships, and optimization of a novel class of fatty acid synthase (FASN) inhibitors is reported. High throughput screening identified a series of substituted piperazines with structural features that enable interactions with many of the potency-driving regions of the FASN KR domain binding site. Derived from this series was FT113, a compound with potent biochemical and cellular activity, which translated into excellent activity in in vivo models. 相似文献
18.
Chen P Norris D Das J Spergel SH Wityak J Leith L Zhao R Chen BC Pitt S Pang S Shen DR Zhang R De Fex HF Doweyko AM McIntyre KW Shuster DJ Behnia K Schieven GL Barrish JC 《Bioorganic & medicinal chemistry letters》2004,14(24):6061-6066
A series of substituted 2-(aminoheteroaryl)-thiazole-5-carboxamide analogs have been synthesized as novel, potent inhibitors of the Src-family kinase p56Lck. Among them, compound 2 displayed superior in vitro potency and excellent in vivo efficacy. 相似文献
19.
DD Li F Fang JR Li QR Du J Sun HB Gong HL Zhu 《Bioorganic & medicinal chemistry letters》2012,22(18):5870-5875
It had been reported that some dioxygenated rings fusing with the quinazoline scaffold could lead to new EGFR inhibitors. Based on this, several kinds of oxygenated alkane quinazoline derivatives were synthetized and evaluated as EGFR inhibitors. Their antiproliferative activities were tested against four cancer cell lines: A431, MCF-7, A549, and B16-F10. Most derivatives could counteract EGF-induced EGFR phosphorylation, and their potency was comparable to the reference compound Erlotinib. The size of the fused dioxygenated ring was crucial for the biological activity and the heptatomic ring derivative 19 showed potent in vitro inhibitory activity in the enzymatic assay as well as in the cellular assay. 相似文献
20.
《Bioorganic & medicinal chemistry letters》2020,30(18):127393
Spleen Tyrosine Kinase (SYK) is a well-studied enzyme with therapeutic applications in oncology and autoimmune diseases. We identified an azabenzimidazole (ABI) series of SYK inhibitors by mining activity data of 86,000 compounds from legacy biochemical assays with SYK and other homologous kinases as target enzymes. A structure-based design and hybridization approach was then used to improve the potency and kinase selectivity of the hits. Lead compound 23 from this novel ABI series has a SYK IC50 = 0.21 nM in a biochemical assay and inhibits growth of SUDHL-4 cells at a GI50 = 210 nM. 相似文献