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1.
《Bioorganic & medicinal chemistry letters》2014,24(15):3609-3613
A unified strategy was conceived and implemented to deliver conformationally constrained anilides based on their preferred cis-amide conformers. The imidazole/triazole mimicing amide bonds were designed, building upon an earlier discovery of a novel series of tricyclic lactams MK2 kinase inhibitors. This approach enabled rapid, modular synthesis of structurally novel analogs. The efficient SAR development led to the discovery of low molecular weight and potent MK2 non-ATP competitive inhibitors with good ligand efficiency, which led to improved permeability and oral exposure in rats. 相似文献
2.
Schlapbach A Feifel R Hawtin S Heng R Koch G Moebitz H Revesz L Scheufler C Velcicky J Waelchli R Huppertz C 《Bioorganic & medicinal chemistry letters》2008,18(23):6142-6146
Pyrrolo-pyrimidones of the general structure 1 were synthesized and evaluated for their potential as MK2 inhibitors. Potent derivatives were discovered which inhibit MK2 in the nanomolar range and show potent inhibition of cytokine release from LPS-stimulated monocytes. These derivatives were shown to inhibit phosphorylation of hsp27, a downstream target of MK2 and are modestly selective in a panel of 28 kinases. 相似文献
3.
Dong Xiao Anandan Palani Xianhai Huang Michael Sofolarides Wei Zhou Xiao Chen Robert Aslanian Zhuyan Guo James Fossetta Fang Tian Prashant Trivedi Peter Spacciapoli Charles E. Whitehurst Daniel Lundell 《Bioorganic & medicinal chemistry letters》2013,23(11):3262-3266
Conformation restriction of linear N-alkylanilide MK2 inhibitors to their E-conformer was developed. This strategy enabled rapid advance in identifying a series of potent non-ATP competitive inhibitors that exhibited cell based activity in anti-TNFα assay. 相似文献
4.
Rickert KW Schaber M Torrent M Neilson LA Tasber ES Garbaccio R Coleman PJ Harvey D Zhang Y Yang Y Marshall G Lee L Walsh ES Hamilton K Buser CA 《Archives of biochemistry and biophysics》2008,469(2):220-231
The kinesin spindle protein (KSP, also known as Eg5) is essential for the proper separation of spindle poles during mitosis, and inhibition results in mitotic arrest and the formation of characteristic monoaster spindles. Several distinct classes of KSP inhibitors have been described previously in the public and patent literature. However, most appear to share a common induced-fit allosteric binding site, suggesting a common mechanism of inhibition. In a high-throughput screen for inhibitors of KSP, a novel class of thiazole-containing inhibitors was identified. Unlike the previously described allosteric KSP inhibitors, the thiazoles described here show ATP competitive kinetic behavior, consistent with binding within the nucleotide binding pocket. Although they bind to a pocket that is highly conserved across kinesins, these molecules exhibit significant selectivity for KSP over other kinesins and other ATP-utilizing enzymes. Several of these compounds are active in cells and produce a phenotype similar to that observed with previously published allosteric inhibitors of KSP. 相似文献
5.
Pierre F Regan CF Chevrel MC Siddiqui-Jain A Macalino D Streiner N Drygin D Haddach M O'Brien SE Rice WG Ryckman DM 《Bioorganic & medicinal chemistry letters》2012,22(9):3327-3331
A novel family of potent dual inhibitors of CK2 and the Pim kinases was discovered by modifying the scaffolds of tricyclic Pim inhibitors. Several analogs were active at single digit nanomolar IC(50) values against CK2 and the Pim isoforms Pim-1 and Pim-2. The molecules displayed antiproliferative activity in various cell phenotypes in the low micromolar and submicromolar range, providing an excellent starting point for further drug discovery optimization. 相似文献
6.
Abraham S Hadd MJ Tran L Vickers T Sindac J Milanov ZV Holladay MW Bhagwat SS Hua H Ford Pulido JM Cramer MD Gitnick D James J Dao A Belli B Armstrong RC Treiber DK Liu G 《Bioorganic & medicinal chemistry letters》2011,21(18):5296-5300
The synthesis and SAR for a novel series of pyrrolotriazines as pan-Aurora kinase inhibitors are described. Optimization of the cyclopropane carboxamide terminus of lead compound 1 resulted in analogs with high cellular activity and improved rat PK profiles. Notably, compound 17l demonstrated tumor growth inhibition in a mouse xenograft model. 相似文献
7.
Watterson SH Carlsen M Dhar TG Shen Z Pitts WJ Guo J Gu HH Norris D Chorba J Chen P Cheney D Witmer M Fleener CA Rouleau K Townsend R Hollenbaugh DL Iwanowicz EJ 《Bioorganic & medicinal chemistry letters》2003,13(3):543-546
A series of novel quinolone-based small molecule inhibitors of inosine monophosphate dehydrogenase (IMPDH) was explored. The synthesis and the structure-activity relationships (SARs) derived from in vitro studies are described. 相似文献
8.
Bingham AH Davenport RJ Gowers L Knight RL Lowe C Owen DA Parry DM Pitt WR 《Bioorganic & medicinal chemistry letters》2004,14(2):409-412
A novel series of aminopyrimidine IKK2 inhibitors have been developed which show excellent in vitro inhibition of this enzyme and good selectivity over the IKK1 isoform. The relative potency and selectivity of these compounds has been rationalized using QSAR and structure-based modelling. 相似文献
9.
Sørensen MD Blaehr LK Christensen MK Høyer T Latini S Hjarnaa PJ Björkling F 《Bioorganic & medicinal chemistry》2003,11(24):5461-5484
The design, synthesis, and structure–activity relationship (SAR) of a series of novel nonpeptidic cyclic phosphon- and phosphinamide-based hydroxamic acids as inhibitors of matrix metalloproteinases MMP-1, MMP-3, and MMP-9 are presented. Based on modelling studies and X-ray analysis, a model of the binding mode of these novel compounds in the MMP active site was obtained. This model provided a rational explanation for the observed SAR data, which included a systematic study of different S1′ directed substituents, zinc-complexing groups, chirality, and variation of the cyclic phosphon- and phosphinamide rings. The in vivo effect of four compounds in a human fibrosarcoma mouse model (HT1080) was evaluated and compared to that of a reference compound, Prinomastat. Inhibition of tumour growth was observed for all four compounds. 相似文献
10.
Henrich CJ Bokesch HR Dean M Bates SE Robey RW Goncharova EI Wilson JA McMahon JB 《Journal of biomolecular screening》2006,11(2):176-183
ABCG2 is a member of the adenosine triphosphate (ATP)-binding cassette family of multidrug transporters associated with resistance of tumor cells to many cytotoxic agents. Evaluation of modulators of ABCG2 activity has relied on methods such as drug sensitization, biochemical characterization, and transport studies. To search for novel inhibitors of ABCG2, a fluorescent cell-based assay was developed for application in high-throughput screening. Accumulation of pheophorbide a (PhA), an ABCG2-specific substrate, forms the basis for the assay in NCI-H460/MX20 cells overexpressing wild-type ABCG2. Treatment of these cells with 10 microM fumitremorgin C (FTC), a specific ABCG2 inhibitor, increased cell accumulation of PhA to 5.6 times control (Z' 0.5). Validation included confirmation with known ABCG2 inhibitors: FTC, novobiocin, tariquidar, and quercetin. Verapamil, reported to inhibit P-glycoprotein but not ABCG2, had insignificant activity. Screening of a library of 3523 natural products identified 11 compounds with high activity (> or = 50% of FTC, confirmed by reassay), including 3 flavonoids, members of a family of compounds that include ABCG2 inhibitors. One of the inhibitors detected, eupatin, was moderately potent (IC50 of 2.2 microM) and, like FTC, restored sensitivity of resistant cells to mitoxantrone. Application of this assay to other libraries of synthetic compounds and natural products is expected to identify novel inhibitors of ABCG2 activity. 相似文献
11.
Luk KC Simcox ME Schutt A Rowan K Thompson T Chen Y Kammlott U DePinto W Dunten P Dermatakis A 《Bioorganic & medicinal chemistry letters》2004,14(4):913-917
A novel series of oxindole-type inhibitors of CDK2 that have heteroatom substituted alkynyl moieties at their C-4 position is described. These novel 4-alkynyl-substituted inhibitors have superior potency relative to their parent compound in free enzyme and in cell based assays. The crystal structure of CDK2 in complex with one of these analogues was determined and gives insight to their increased potency. The biochemical evaluation of a representative derivative is also described. 相似文献
12.
NS Cutshall R Onrust A Rohde S Gragerov L Hamilton K Harbol HR Shen S McKee C Zuta G Gragerova V Florio TN Wheeler JL Gage 《Bioorganic & medicinal chemistry letters》2012,22(17):5595-5599
A series of 2-methoxyacylhydrazones were optimized to yield compounds with high affinity for PDE10A. Several compounds demonstrated efficacy in animal models of schizophrenia, including conditioned avoidance response and a pro-psychotic phencyclidine hyperactivity model. 相似文献
13.
《Bioorganic & medicinal chemistry letters》2020,30(22):127523
Hybridisation of amino-pyrimidine based SYK inhibitors (e.g. 1a) with previously reported diamine-based SYK inhibitors (e.g. TAK-659) led to the identification and optimisation of a novel pyrimidine-based series of potent and selective SYK inhibitors, where the original aminomethylene group was replaced by a 3,4-diaminotetrahydropyran group. The initial compound 5 achieved excellent SYK potency. However, it suffered from poor permeability and modest kinase selectivity. Further modifications of the 3,4-diaminotetrahydropyran group were identified and the interactions of those groups with Asp512 were characterised by protein X-ray crystallography. Further optimisation of this series saw mixed results where permeability and kinase selectivity were increased and oral bioavailability was achieved in the series, but at the expense of potent hERG inhibition. 相似文献
14.
Cyclin-dependent kinases (CDKs) are essential in the control of cell cycle progression. Inhibition of CDKs represents a new approach for pharmacological intervention in the treatment of a variety of proliferative diseases, especially cancer. Based on the crystal structure of CDK2 in complex with an imidazole indolinone compound 1 (SU9516), lead optimization through modeling, synthesis, and SAR studies has led to the discovery of a novel series of pyrrolyllactone and pyrrolyllactam indolinones as potent CDK2 inhibitors. 相似文献
15.
Bi X Lopez C Bacchi CJ Rattendi D Woster PM 《Bioorganic & medicinal chemistry letters》2006,16(12):3229-3232
A series of polyaminoguanidines and polyaminobiguanides were synthesized and evaluated as potential antitrypanosomal agents. These analogues inhibit trypanothione reductase (TR) with IC50 values as low as 0.95 microM, but do not inhibit the closely related human enzyme glutathione reductase (GR). The most effective analogues, 7a, 7b and 8d, inhibited parasitic growth in vitro with IC50 values of 0.18, 0.09 and 0.18 microM, respectively. These agents represent a promising new class of potential antitrypanosomal agents. 相似文献
16.
《Bioorganic & medicinal chemistry letters》2019,29(23):126709
Four series of berberine derivatives were designed and synthesized. All the synthetic compounds were screened for in vitro glucose consumption activity in HepG2 cell lines. The results showed that most of the tested compounds exhibited potent hypoglycemic activity, and the most potent compound 20b exhibited its potency by 3.23-fold of berberine, 1.39-fold of metformin and 1.20-fold of rosiglitazone, respectively. Western blot assay indicated these novel berberine-based derivatives executed their glucose-decreasing activity via the activation of AMPK pathway. 相似文献
17.
Charlotte Schou Erik R. Ottosen Hans Jørgen Petersen Fredrik Björkling Scilla Latini Pernille V. Hjarnaa Erik Bramm Lise Binderup 《Bioorganic & medicinal chemistry letters》1997,7(24):616-3100
4-Pyridyl cyanoguanidines with hydrophobic aromatic side chains showed potent antiproliferative activity in the human breast and lung cancer cell lines MCF-7, NYH and H460. In vivo, treatment with N-(6-chlorophenoxyhexyl)-N′-cyano-N″-4-pyridylguanidine (18, 20 mg/kg/day po.), gave a complete remission of tumours in a model of NYH inoculated nude mice. 相似文献
18.
Davis T Bagley MC Dix MC Murziani PG Rokicki MJ Widdowson CS Zayed JM Bachler MA Kipling D 《Bioorganic & medicinal chemistry letters》2007,17(24):6832-6835
A benzopyranopyridine inhibitor of mitogen-activated protein kinase-activated protein kinase 2 (MK2) is prepared rapidly and efficiently in one step using microwave dielectric heating, whereas a substrate-selective p38 MAPK inhibitor was prepared using conventional heating techniques. The former had MK2 inhibitory activity above 2.5 μM concentration, whereas the latter showed no MK2 inhibition at 10 μM. However, rather than rescuing the reduced cellular growth rate and aged morphology of hTERT-immortalised WS dermal fibroblasts, both induce a state resembling stress-induced cellular senescence, suggesting that these inhibitors may have limited therapeutic use. 相似文献
19.
Deaton DN Hassell AM McFadyen RB Miller AB Miller LR Shewchuk LM Tavares FX Willard DH Wright LL 《Bioorganic & medicinal chemistry letters》2005,15(7):1815-1819
Starting from a PDE IV inhibitor hit derived from high throughput screening of the compound collection, a key pyrrolidine cyanamide pharmacophore was identified. Modifications of the pyrrolidine ring produced enhancements in cathepsin K inhibition. An X-ray co-crystal structure of a cyanamide with cathepsin K confirmed the mode of inhibition. 相似文献
20.
Mostafa M. Ghorab Fatma A. Ragab Helmy I. Heiba Marwa G. El-Gazzar Mostafa G.M. El-Gazzar 《Bioorganic & medicinal chemistry letters》2018,28(9):1464-1470
In this study, novel series of thioureido-benzenesulfonamide derivatives bearing an enaminone linker either meta or para oriented and having terminal linear or substituted aromatic or heteroaromatic ring system 5–16a,b were designed and synthesized based on the general pharmacophoric features of type II VEGFR2 inhibitors. Evaluation of the synthesized compounds against HEPG2 hepatocellular carcinoma cells in vitro identified compounds 5b, 6b and 10–13b as most active anticancer agents with IC50 equal to 0.12, 0.29, 0.58, 0.44, 0.42 and 0.66?µM, respectively. These compounds were evaluated for their ability to in vitro inhibit VEGFR2 kinase enzyme. The results demonstrated highly potent dose-related VEGFR2 inhibition with IC50 values in nanomolar range (33, 57, 210, 37, 37 and 220?nM, respectively). The radiosensitizing ability of the most promising compounds was studied which showed an increase in the cell killing effect of radiation after combination with the synthesized compounds which revealed lowered IC50 by nearly 50%. Molecular docking for the most potent compounds was performed to predict their possible binding mode within VEGFR2 active site and they showed binding affinity in a similar way to sorafenib. 相似文献