共查询到20条相似文献,搜索用时 15 毫秒
1.
Saniya Virani Zhongxing Liang Younghyoun Yoon Hyunsuk Shim Suazette R. Mooring 《Bioorganic & medicinal chemistry letters》2019,29(2):220-224
CXCR4 and its cognate ligand CXCL12 has been linked to various pathways such as cancer metastasis, inflammation, HIV-1 proliferation, and auto-immune diseases. Small molecules have shown potential as CXCR4 inhibitors and modulators, and therefore can mitigate diseases related to the CXCR4-CXCL12 pathway. We have designed and synthesized a series of 2,5-diamino and 2,5-dianilinomethyl pyridine derivatives as potential CXCR4 antagonists. Thirteen compounds have an effective concentration (EC) of 100?nM or less in a binding affinity assay and nine of these have at least 75% inhibition of invasion in Matrigel binding assay. Compounds 3l, 7f, 7j, and 7p show a minimal reduction in inflammation when carrageenan paw edema test is conducted. Overall, these compounds show potential as CXCR4 antagonist. 相似文献
2.
Wen-Hsing Lin John T.-A. Hsu Shu-Yi Hsieh Chiung-Tong Chen Jen-Shin Song Shih-Chieh Yen Tsu Hsu Cheng-Tai Lu Chun-Hwa Chen Ling-Hui Chou Yung-Ning Yang Ching-Hui Chiu Ching-Ping Chen Ya-Ju Tseng Kuei-Jung Yen Ching-Fang Yeh Yu-Sheng Chao Teng-Kuang Yeh Weir-Torn Jiaang 《Bioorganic & medicinal chemistry》2013,21(11):2856-2867
Preclinical investigations and early clinical trials suggest that FLT3 inhibitors are a viable therapy for acute myeloid leukemia. However, early clinical data have been underwhelming due to incomplete inhibition of FLT3. We have developed 3-phenyl-1H-5-pyrazolylamine as an efficient template for kinase inhibitors. Structure–activity relationships led to the discovery of sulfonamide, carbamate and urea series of FLT3 inhibitors. Previous studies showed that the sulfonamide 4 and carbamate 5 series were potent and selective FLT3 inhibitors with good in vivo efficacy. Herein, we describe the urea series, which we found to be potent inhibitors of FLT3 and VEGFR2. Some inhibited growth of FLT3-mutated MOLM-13 cells more strongly than the FLT3 inhibitors sorafenib (2) and ABT-869 (3). In preliminary in vivo toxicity studies of the four most active compounds, 10f was found to be the least toxic. A further in vivo efficacy study demonstrated that 10f achieved complete tumor regression in a higher proportion of MOLM-13 xenograft mice than 4 and 5 (70% vs 10% and 40%). These results show that compound 10f possesses improved pharmacologic and selectivity profiles and could be more effective than previously disclosed FLT3 inhibitors in the treatment of acute myeloid leukemia. 相似文献
3.
《Bioorganic & medicinal chemistry letters》2020,30(13):127197
A novel series of ethyl ketone based HDACs 1, 2, and 3 selective inhibitors have been identified with good enzymatic and cellular activity and high selectivity over HDACs 6 and 8. These inhibitors contain a spirobicyclic group in the amide region. Compound 13 stands out as a lead due to its good potency, high selectivity, and reasonable rat and dog PK. Compounds 33 and 34 show good potency and rat PK profiles as well. 相似文献
4.
Shao Y Anilkumar GN Carroll CD Dong G Hall JW Hobbs DW Jiang Y Jenh CH Kim SH Kozlowski JA McGuinness BF Rosenblum SB Schulman I Shih NY Shu Y Wong MK Yu W Zawacki LG Zeng Q 《Bioorganic & medicinal chemistry letters》2011,21(5):1527-1531
The structure-human CXCR3 binding affinity relationship of a series of pyridyl-piperazinyl-piperidine derivatives was explored. The optimization campaign highlighted the pronounced effect of 2′-piperazine substitution on CXCR3 receptor affinity. Analog 18j, harboring a 2′(S)-ethylpiperazine moiety, exhibited a human CXCR3 IC50 of 0.2 nM. 相似文献
5.
《Bioorganic & medicinal chemistry letters》2014,24(4):1116-1121
We designed a series of anilino-indoylmaleimides based on structural elements from literature JAK3 inhibitors 3 and 4, and our lead 5. These new compounds were tested as inhibitors of JAKs 1, 2 and 3 and TYK2 for therapeutic intervention in rheumatoid arthritis (RA). Our requirements, based on current scientific rationale for optimum efficacy against RA with reduced side effects, was for potent, mixed JAK1 and 3 inhibition, and selectivity over JAK2. Our efforts yielded a potent JAK3 inhibitor 11d and its eutomer 11e. These compounds were highly selective for inhibition of JAK3 over JAK2 and TYK. The compounds displayed only modest JAK1 inhibition. 相似文献
6.
To search for effective and selective inhibitors of carboxylesterase (CES), a series of 3-oxo-2-tolylhydrazinylidene-4,4,4-trifluorobutanoates bearing higher or natural alcohol moieties was synthesized via pre-transesterification of ethyl trifluoroacetylacetate with alcohols to isolate transesterificated oxoesters as lithium salts, which were then subjected to azo coupling with tolyldiazonium chloride. Inhibitory activity against porcine liver CES, along with two structurally related serine hydrolases, acetylcholinesterase and butyrylcholinesterase, were investigated using enzyme kinetics and molecular docking. Kinetics studies demonstrated that the tested keto-esters are reversible and selective mixed-type CES inhibitors. Analysis of X-ray crystallographic data together with our IR and NMR spectra and QM calculations indicated that the Z-isomers were the most stable. The kinetic data were well explained by the molecular docking results of the Z-isomers, which showed specific binding of the compounds in the CES catalytic active site with carbonyl oxygen atoms in the oxyanion hole and non-specific binding outside it. Some compounds were studied as inhibitors of the main human isozymes involved in biotransformation of ester-containing drugs, hCES1 and hCES2. Esters of geraniol (3d) and adamantol (3e) proved to be highly active and selective inhibitors of hCES2, inhibiting the enzyme in the nanomolar range, whereas esters of borneol (3f) and isoborneol (3g) were more active and selective against hCES1. Computational ADMET studies revealed that all test compounds had excellent intestinal absorption, medium blood-brain barrier permeability, and low hERG liability risks. Moreover, all test compounds possessed radical-scavenging properties and low acute toxicity. Overall, the results indicate that members of this novel series of esters have the potential to be good candidates as hCES1 or hCES2 inhibitors for biomedicinal applications. 相似文献
7.
《Bioorganic & medicinal chemistry letters》2014,24(23):5493-5496
2-Aminopyrimidin-4(1H)-one was proposed as the novel bioisostere of urea. Bioisosteric replacement of the reported urea series of the CXCR2 antagonists with 2-aminopyrimidin-4(1H)-ones led to the discovery of the novel and potent CXCR2 antagonist 3e. 2-Aminopyrimidin-4(1H)-one derivative 3e demonstrated a good developability profile (reasonable solubility and high permeability) and superior chemical stability especially in simulated gastric fluid (SGF) compared with ureas. 相似文献
8.
2-Dimethylaminomethylene-1-benzosuberone 1 was coupled with diazotized aniline derivatives to afford a series of the hitherto unreported 2-arylazo-1-benzosuberones 3a–i. The tautomeric structure and the effect of substituents on the tautomeric form (s) of the products 3a–i were discussed. Similar coupling of the enaminone 1 with diazonium salts of heterocyclic amines gave the respective fused azolotriazino-benzosuberones. Some of the newly synthesized compounds showed potent antimicrobial, anti-HCV, antioxidant, antitumor (as topoisomerase I inhibitors), and antimicrobial activities. 相似文献
9.
DeMarco SJ Henze H Lederer A Moehle K Mukherjee R Romagnoli B Robinson JA Brianza F Gombert FO Lociuro S Ludin C Vrijbloed JW Zumbrunn J Obrecht JP Obrecht D Brondani V Hamy F Klimkait T 《Bioorganic & medicinal chemistry》2006,14(24):8396-8404
Novel highly potent CXCR4 inhibitors with good pharmacokinetic properties were designed and optimized starting from the naturally occurring β-hairpin peptide polyphemusin II. The design involved incorporating important residues from polyphemusin II into a macrocyclic template-bound β-hairpin mimetic. Using a parallel synthesis approach, the potency and ADME properties of the mimetics were optimized in iterative cycles, resulting in the CXCR4 inhibitors POL2438 and POL3026. The inhibitory potencies of these compounds were confirmed in a series of HIV-1 invasion assays in vitro. POL3026 showed excellent plasma stability, high selectivity for CXCR4, favorable pharmacokinetic properties in the dog, and thus has the potential to become a therapeutic compound for application in the treatment of HIV infections (as an entry inhibitor), cancer (for angiogenesis suppression and inhibition of metastasis), inflammation, and in stem cell transplant therapy. 相似文献
10.
《Bioorganic & medicinal chemistry》2014,22(23):6625-6637
A series of simplified ring-opened resorcylic acid lactone (RAL) derivatives were conveniently synthesized to target FLT3 and its mutants either irreversibly or reversibly. Our design of covalent FLT3 inhibitors is based on cis-enone RALs (e.g., L-783,277) that have a β-resorcylic acid as the core structure. The designed compounds contain three types of Michael acceptors (acrylamide, vinylsulfonamide and maleimide) as potential covalent traps of a cysteine residue at the binding site of kinases. A variety of functional substitutions were also introduced to maximize the binding interactions. Biological evaluations revealed that compound 17, despite the presence of a highly reactive maleimide Michael acceptor, is a potent covalent FLT3 inhibitor which shows some specificity in cellular assays. On the other hand, compounds 2 and 6 containing acrylamide or vinylsulfonamide groups are reversible towards FLT3 binding, and are potent and selective inhibitors of mutant FLT3-ITD versus wt-FLT3. They also inhibit cell proliferation in FLT3-ITD expressing cell line MV-4-11 as compared to wt-FLT3 expressing cell line THP-1 and non-FLT3 cell lines (K562, HL60 and Hek-293T). 相似文献
11.
A series of novel naproxen analogues containing 3-aryl-1,2,4-oxadiazoles moiety (4b-g) and their reaction intermediates aryl carboximidamides moiety (3b-g) was synthesized and evaluated in vitro as dual COXs/15-LOX inhibitors. Compounds 3b-g exhibited superior inhibitory activity than celecoxib as COX-2 inhibitors. Compounds 3b-d and 3g were the most potent COX-2 inhibitors with IC50 range of 6.4 – 8.13 nM and higher selectivity indexes (3b, SI = 26.19; 3c, SI = 13.73; 3d, SI = 29.27; 3g, SI = 18.00) comparing to celecoxib (IC50 = 42.60 nM, SI = 8.05). Regarding 15-LOX inhibitory activity, compounds belonging to aryl carboximidamide backbone 3b-e and 3g were the most potent with IC50 range of 1.77–4.91 nM comparing to meclofenamate sodium (IC50 = 5.64 µM). Data revealed that The levels of NO released by aryl carboximidamides 3b-g were more higher than 3-aryl-1,2,4-oxadiazole derivatives 4b-g, which correlated well with their COX-2 inhibitory activities. 相似文献
12.
Design,synthesis, and biological evaluation of some novel 4-aminoquinazolines as Pan-PI3K inhibitors
Huai-Wei Ding Shu Wang Xiao-Chun Qin Jian Wang Hong-Rui Song Qing-Chun Zhao Shao-Jiang Song 《Bioorganic & medicinal chemistry》2019,27(13):2729-2740
A series of 4-aminoquinazolines derivatives containing hydrophilic group were designed and identified as potent Pan-PI3K inhibitors in this study. The results of antiproliferative assays in vitro showed that this series of compounds had strong inhibition of tumor growth, especially compound 7b for MCF-7 cells but weak inhibition to normal cells. PI3K kinase assay showed that 7b had high activity for three PI3K isoforms with the IC50 values of picomole. The western blot assay indicated that 7b could decrease the phospho-Akt (S473) in a dose-dependent manner. Further experiments showed that 7b could induce apoptosis in MCF-7 cells. Four key hydrogen bonding interactions were found in the docking of 7b with PI3K kinase. All these results suggested that 7b is a potent PI3K inhibitor and could be considered as a potential candidate for the development of anticancer agents. 相似文献
13.
Xiaohui Du Darin J. Gustin Xiaoqi Chen Jason Duquette Lawrence R. McGee Zhulun Wang Karen Ebsworth Kirk Henne Bryan Lemon Ji Ma Shichang Miao Emmanuel Sabalan Timothy J. Sullivan George Tonn Tassie L. Collins Julio C. Medina 《Bioorganic & medicinal chemistry letters》2009,19(17):5200-5204
A general way of improving the potency of CXCR3 antagonists with fused hetero-bicyclic cores was identified. Optimization efforts led to the discovery of a series of imidazo-pyrazine derivatives with improved pharmacokinetic properties in addition to increased potency. The efficacy of the lead compound 21 is evaluated in a mouse lung inflammation model. 相似文献
14.
Saul Jaime-Figueroa Javier De Vicente Johannes Hermann Alam Jahangir Sue Jin Andreas Kuglstatter Stephen M. Lynch John Menke Linghao Niu Vaishali Patel Ada Shao Michael Soth Minh Diem Vu Calvin Yee 《Bioorganic & medicinal chemistry letters》2013,23(9):2522-2526
We report the discovery of a novel series of ATP-competitive Janus kinase 3 (JAK3) inhibitors based on the 5H-pyrrolo[2,3-b]pyrazine scaffold. The initial leads in this series, compounds 1a and 1h, showed promising potencies, but a lack of selectivity against other isoforms in the JAK family. Computational and crystallographic analysis suggested that the phenyl ether moiety possessed a favorable vector to achieve selectivity. Exploration of this vector resulted in the identification of 12b and 12d, as potent JAK3 inhibitors, demonstrating improved JAK family and kinase selectivity. 相似文献
15.
《Bioorganic & medicinal chemistry》2016,24(21):5393-5399
CXCR4 dimerization has been widely demonstrated both biologically and structurally. This paper mainly focused on the development of structure-based dimeric ligands that target CXCL12–CXCR4 interaction and signaling. This study presents the design and synthesis of a series of [PEG]n linked dimeric ligands of CXCR4 based on the knowledge of the homodimeric crystal structure of CXCR4 and our well established platform of chemistry and bioassays for CXCR4. These new ligands include [PEG]n linked homodimeric or heterodimeric peptides consisting of either two DV3-derived moieties (where DV3 is an all-d-amino acid analog of N-terminal modules of 1–10 (V3) residues of vMIP-II) or hybrids of DV3 moieties and CXCL121–8. Among a total of 24 peptide ligands, four antagonists and three agonists showed good CXCR4 binding affinity, with IC50 values of <50 nM and <800 nM, respectively. Chemotaxis and calcium mobilization assays with SUP-T1 cells further identified two promising lead modulators of CXCR4: ligand 4, a [PEG3]2 linked homodimeric DV3, was an effective CXCR4 antagonist (IC50 = 22 nM); and ligand 21, a [PEG3]2 linked heterodimeric DV3–CXCL121–8, was an effective CXCR4 agonist (IC50 = 407 nM). These dimeric CXCR4 modulators represent new molecular probes and therapeutics that effectively modulate CXCL12–CXCR4 interaction and function. 相似文献
16.
Mohamed A.H. Ismail M. Nabil Aboul-Enein Khaled A.M. Abouzid Dalal A. Abou El Ella Nasser S.M. Ismail 《Bioorganic & medicinal chemistry》2009,17(10):3739-3746
A series of new 3-mercapto-2-methyl-propanoyl-pyrrolidine derivatives (V, VIa–e) were designed. A new validated ACE inhibitors pharmacophore model (hypothesis) was generated for the first time in this research from the biologically active (frozen) conformation of Lisinopril–Human ACE complex that was downloaded from PDB, using stepwise technique of CATALYST modules. The molecular modeling compare–fit study of the designed molecules (V, VIa–e), with such ACE inhibitors hypothesis was fulfilled, and several compounds showed significant high simulation fit values. The compounds with high fit values were synthesized and biologically evaluated in vivo as hypotensive agents. It appears that the in vivo hypotensive activity of compounds V, VIa, VIb, and VIe was consistent with their molecular modeling results, and compound VIe showed the highest activity in comparison to Captopril. 相似文献
17.
Jonathan Z. Ho Odile E. Levy Tony S. Gibson Khanh Nguyen J. Edward Semple 《Bioorganic & medicinal chemistry letters》1999,9(24):2925
A series of novel FXa inhibitors 2a-m and 3a-f was discovered that feature heterocyclic carboxamides tethered to a d-diaminobutyric acid sidechain. These neutral amide derivatives serve as novel P3 d-arginine mimics. Pyrazine carboxamide scaffolds afforded the most potent FXa inhibitors (e.g., 2b IC50 = 4.6 nM). The synthesis and biological activity of two focused libraries are reported. 相似文献
18.
A series of m-alkyl α,α,α-trifluoroacetophenones (1–5) was synthesized and evaluated as inhibitors of acetylcholinesterase from Torpedo california. All ketones (1–5) were found to be potent inhibitors of the enzyme; m-t-butyl α,α,α-trifluoroacetophenone (4) was the most potent inhibitor with a Ki value of 3.7 pM. 相似文献
19.
《Bioorganic & medicinal chemistry letters》2014,24(22):5181-5184
Based on the anti-mycobacterial activity of various acid hydrazides, a series of substituted 3-hydrazinyl-3-oxo-propanamides has been designed. The target compounds have been synthesized from diethylmalonate using substituted amines and hydrazine hydrate in ethanol. Computational studies and anti-tubercular activity screenings were undertaken to test their inhibitory effect on protein kinase PknB from Mycobacterium tuberculosis. Binding poses of the compounds were energetically favorable and showed good interactions with active site residues. Designed molecules obey the Lipinski’s rule of 5 and gave moderate to good drug likeness score. Among the sixteen compounds (1–16) taken for in silico and in vitro studies, 3 compounds (11, 12 and 15) have shown good binding energies along with exhibiting good anti-tubercular activity and thus may be considered as a good inhibitors of PknB. 相似文献
20.
《Bioorganic & medicinal chemistry letters》2014,24(24):5721-5726
A new class of Janus kinase (JAK) inhibitors was discovered using a rationally designed pyrrolo[1,2-b]pyridazine-3-carboxamide scaffold. Preliminary studies identified (R)-(2,2-dimethylcyclopentyl)amine as a preferred C4 substituent on the pyrrolopyridazine core (3b). Incorporation of amino group to 3-position of the cyclopentane ring resulted in a series of JAK3 inhibitors (4g–4j) that potently inhibited IFNγ production in an IL2-induced whole blood assay and displayed high functional selectivity for JAK3–JAK1 pathway relative to JAK2. Further modifications led to the discovery of an orally bioavailable (2-fluoro-2-methylcyclopentyl)amino analogue 5g which is a nanomolar inhibitor of both JAK3 and TYK2, functionally selective for the JAK3–JAK1 pathway versus JAK2, and active in a human whole blood assay. 相似文献