共查询到20条相似文献,搜索用时 11 毫秒
1.
Christine Yang Hong C. Shen Zhicai Wu Hong D. Chu Jason M. Cox Jaume Balsells Alejandro Crespo Patricia Brown Beata Zamlynny Judyann Wiltsie Joseph Clemas Jack Gibson Lisa Contino JeanMarie Lisnock Gaochao Zhou Margarita Garcia-Calvo Tom Bateman Ling Xu Peter Sinclair 《Bioorganic & medicinal chemistry letters》2013,23(15):4388-4392
Novel oxazolidinedione analogs were discovered as potent and selective mineralocorticoid receptor (MR) antagonists. Structure–activity relationship (SAR) studies were focused on improving the potency and microsomal stability. Selected compounds demonstrated excellent MR activity, reasonable nuclear hormone receptor selectivity, and acceptable rat pharmacokinetics. 相似文献
2.
Ueno H Yokota K Hoshi J Yasue K Hayashi M Uchida I Aisaka K Hase Y Katoh S Cho H 《Bioorganic & medicinal chemistry letters》2005,15(1):185-189
A series of novel 2,7-disubstituted tetrahydroisoquinoline derivatives were designed and synthesized. Among these derivatives, compounds 1 and 2 (JTV-803) exhibited potent inhibitory activity against FXa and good selectivity with respect to other serine proteases (thrombin, plasmin, and trypsin). In addition, compound 2 exhibited potent anti-FXa activity after intravenous and oral administration to cynomolgus monkey, and showed a dose-dependent antithrombotic effect in a rat model of venous thrombosis. 相似文献
3.
Yongjian Zang Dongxiao Hao He Wang Huadong Liu 《Journal of biomolecular structure & dynamics》2020,38(15):4617-4624
Communicated by Ramaswamy H. Sarma 相似文献
4.
Haga Y Mizutani S Naya A Kishino H Iwaasa H Ito M Ito J Moriya M Sato N Takenaga N Ishihara A Tokita S Kanatani A Ohtake N 《Bioorganic & medicinal chemistry》2011,19(2):883-893
The design, synthesis and structure-activity relationships of a novel class of N-phenylpyridone MCH1R antagonists are described. The core part of the N-phenylpyridone structure was newly designed and the side chain moieties that were attached to the core part were extensively explored. As a result of optimization of the N-phenylpyridone leads, we successfully developed the orally available, and brain-penetrable MCH1R selective antagonist 7c, exhibiting excellent anti-obese effect in diet-induced obese (DIO) mice. 相似文献
5.
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
6.
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
7.
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
8.
Ren Sheng Liu Yang Yanchun Zhang Enming Xing Rui Shi Xiaoan Wen Heyao Wang Hongbin Sun 《Bioorganic & medicinal chemistry letters》2018,28(15):2599-2604
GPR120 is an attractive target for the treatment of type 2 diabetes. In this study, a series of biphenyl derivatives were designed, synthesized by hybrid design. The selected compound 6a exhibited potent GPR120 agonist activity (EC50?=?93?nM) and high selectivity over GPR40. The results of oral glucose tolerance test (OGTT) demonstrated that 6a exhibited significant glucose-lowering effect in glucose-loaded ICR male mice. Analysis of the structure–activity relationship is also presented. Compound 6a deserves further biological evaluation and structural modifications. 相似文献
9.
《Bioorganic & medicinal chemistry letters》2020,30(1):126662
Starting from easy accessible pyrazoletetrahydropyran acetals, a series of new pyrazolone spirocyclohexadienone derivatives were synthesized and assayed for antitumor activity. Compound 10s was identified to possess good antitumor activity. It could induce MDA-MB-231 cancer cell apoptosis in a concentration dependent manner and arrest the cell cycle progression mainly at the G1 phase. 相似文献
10.
Maria Scuotto Rana Abdelnabi Selene Collarile Chiara Schiraldi Leen Delang Antonio Massa Salvatore Ferla Andrea Brancale Pieter Leyssen Johan Neyts Rosanna Filosa 《Bioorganic & medicinal chemistry》2017,25(1):327-337
We recently identified indole derivatives (IIIe and IIIf) with anti-chikungunya virus (CHIKV) activities at lower micro molar concentrations and a selective index of inhibition higher than the lead compound Arbidol. Here we highlight new structural information for the optimization of the previously identified lead compounds that contain the indole chemical core. Based on the structural data, a series of indole derivatives was synthesized and tested for their antiviral activity against chikungunya virus in Vero cell culture by a CPE reduction assay.Systematic optimization of the lead compounds resulted in tert-butyl-5-hydroxy-1-methyl-2-(2-trifluoromethysulfynyl)methyl)-indole-3-carboxylate derivative IIc with a 10-fold improved anti-CHIKV inhibitory activity (EC50 = 6.5 ± 1 μM) as compared to Arbidol demonstrating a potent, selective and specific inhibition of CHIKV replication with only a moderate cell protective effect against other related alphaviruses. The reported computational insights, together with the accessible synthetic procedure, pave the road towards the design of novel synthetic derivatives with enhanced anti-viral activities. 相似文献
11.
Hannah J. Winfield Michael M. Cahill Kevin D. OShea Larry T. Pierce Thomas Robert Sandrine Ruchaud Stéphane Bach Pascal Marchand Florence O. McCarthy 《Bioorganic & medicinal chemistry》2018,26(14):4209-4224
Synthesis and biological evaluation of a series of novel indole derivatives as anticancer agents is described. A bisindolylmaleimide template has been derived as a versatile pharmacophore with which to pursue chemical diversification. Starting from maleimide, the introduction of an oxygen to the headgroup (hydroxymaleimide) was initially investigated and the bioactivity assessed by screening of kinase inhibitory activity, identifying substituent derived selectivity. Extension of the hydroxymaleimide template to incorporate substitution of the indole nitrogens was next completed and assessed again by kinase inhibition identifying unique selectivity patterns with respect to GSK-3 and CDK kinases. Subsequently, the anticancer activity of bisindolylmaleimides were assessed using the NCI-60 cell screen, disclosing the discovery of growth inhibitory profiles towards a number of cell lines, such as SNB-75 CNS cancer, A498 and UO-31 renal, MDA MB435 melanoma and a panel of leukemia cell lines. The potential for selective kinase inhibition by modulation of this template is evident and will inform future selective clinical candidates. 相似文献
12.
Takao Suzuki Minoru Moriya Toshihiro Sakamoto Takuya Suga Hiroyuki Kishino Hidekazu Takahashi Makoto Ishikawa Keita Nagai Yumiko Imai Etsuko Sekino Masahiko Ito Hisashi Iwaasa Akane Ishihara Shigeru Tokita Akio Kanatani Nagaaki Sato Takehiro Fukami 《Bioorganic & medicinal chemistry letters》2009,19(11):3072-3077
Optimization of high-throughput screening hit 1a led to the identification of a novel spiro-piperidine class of melanin-concentrating hormone 1 receptor (MCH-1R) antagonists. Compound 3c was identified as a highly potent and selective MCH-1R antagonist, which has an IC50 value of 0.09 nM at hMCH-1R. The synthesis and structure–activity relationships of the novel spiro-piperidine MCH-1R antagonists are described. 相似文献
13.
Liddle J Atkinson FL Barker MD Carter PS Curtis NR Davis RP Douault C Dickson MC Elwes D Garton NS Gray M Hayhow TG Hobbs CI Jones E Leach S Leavens K Lewis HD McCleary S Neu M Patel VK Preston AG Ramirez-Molina C Shipley TJ Skone PA Smithers N Somers DO Walker AL Watson RJ Weingarten GG 《Bioorganic & medicinal chemistry letters》2011,21(20):6188-6194
The lead optimisation of the diaminopyrimidine carboxamide series of spleen tyrosine kinase inhibitors is described. The medicinal chemistry strategy was focused on optimising the human whole blood activity whilst achieving a sufficient margin over liability kinases and hERG activity. GSK143 is a potent and highly selective SYK inhibitor showing good efficacy in the rat Arthus model. 相似文献
14.
Cywin CL Zhao BP McNeil DW Hrapchak M Prokopowicz AS Goldberg DR Morwick TM Gao A Jakes S Kashem M Magolda RL Soll RM Player MR Bobko MA Rinker J DesJarlais RL Winters MP 《Bioorganic & medicinal chemistry letters》2003,13(8):1415-1418
The discovery of novel 5,7-disubstituted[1,6]naphthyridines as potent inhibitors of Spleen Tyrosine Kinase (SYK) is discussed. The SAR reveals the necessity for a 7-aryl group with preference towards para substitution and that this in combination with 5-aminoalkylamino substituents further improved the potency of the compounds. The initial SAR as well as a survey of the other positions is discussed in detail. 相似文献
15.
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
16.
《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
17.
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
18.
Clark RF Zhang T Xin Z Liu G Wang Y Hansen TM Wang X Wang R Zhang X Frevert EU Camp HS Beutel BA Sham HL Gu YG 《Bioorganic & medicinal chemistry letters》2006,16(23):6078-6081
Structure-activity relationships for a recently discovered thiazolyl phenyl ether series of acetyl-CoA carboxylase (ACC) inhibitors were investigated. Preliminary efforts to optimize the series through modification of the distal aryl ether moiety of the lead scaffold resulted in the identification of compounds exhibiting low-nanomolar potency and isozyme-selective ACC2 activity. 相似文献
19.
Iwama S Kitano T Fukuya F Honda Y Sato Y Notake M Morie T 《Bioorganic & medicinal chemistry letters》2004,14(10):2567-2570
A new series of phenylpiperazine-based derivatives with strong antagonistic activity for alpha v beta 3 integrin were synthesized. Of these derivatives, the fluorine-substituted compound 8 showed strong inhibitory activity and high selectivity for alpha v beta 3 integrin receptor (IC(50) = 0.055 nM). In vivo evaluation of the antistenotic effects of 8 indicated that this compound significantly inhibits neointima formation in rat balloon injury model. 相似文献
20.
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