共查询到20条相似文献,搜索用时 31 毫秒
1.
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
2.
Sampath-Kumar Anandan Richard D. Gless 《Bioorganic & medicinal chemistry letters》2010,20(9):2740-2744
The impact of various secondary and tertiary pharmacophores on in vitro potency of soluble epoxide hydrolase (sEH) inhibitors based on the unsymmetrical urea scaffold 1 is discussed. N,N′-Diaryl urea inhibitors of soluble epoxide hydrolase exhibit subtle variations in inhibitory potency depending on the secondary pharmacophore but tolerate considerable structural variation in the second linker/tertiary pharmacophore fragment. 相似文献
3.
Ariamala Gopalsamy Mengxiao Shi Yongbo Hu Frederick Lee Larry Feldberg Eileen Frommer Steven Kim Karen Collins Donald Wojciechowicz Robert Mallon 《Bioorganic & medicinal chemistry letters》2010,20(8):2431-2434
In continuation of our efforts toward hit identification and optimization for a B-Raf kinase project, we have employed a scaffold hopping strategy. The original HTS hit scaffold pyrazolo[1,5-a]pyrimidine was replaced with different thienopyrimidine and thienopyridine scaffolds to append the optimal pharmacophore moieties in order to generate novel B-raf kinase inhibitors with desirable potency and properties. This strategy led to the identification of additional lead compound 11b which had good enzyme and cell potency, while maintaining selectivity over a number of kinases. 相似文献
4.
Nicholas A. Meanwell Owen B. Wallace Haiquan Fang Henry Wang Milind Deshpande Tao Wang Zhiwei Yin Zhongxing Zhang Bradley C. Pearce Jennifer James Kap-Sun Yeung Zhilei Qiu J.J. Kim Wright Zheng Yang Lisa Zadjura Donald L. Tweedie Suresh Yeola Fang Zhao Sunanda Ranadive Brett A. Robinson Pin-fang Lin 《Bioorganic & medicinal chemistry letters》2009,19(7):1977-1981
The effects of introducing simple halogen, alkyl, and alkoxy substituents to the 4, 5, 6 and 7 positions of 1-(4-benzoylpiperazin-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione, an inhibitor of the interaction between HIV gp120 and host cell CD4 receptors, on activity in an HIV entry assay was examined. Small substituents at C-4 generally resulted in increased potency whilst substitution at C-7 was readily tolerated and uniformly produced more potent HIV entry inhibitors. Substituents deployed at C-6 and, particularly, C-5 generally produced a modest to marked weakening of potency compared to the prototype. Small alkyl substituents at N-1 exerted minimal effect on activity whilst increasing the size of the alkyl moiety led to progressively reduced inhibitory properties. These studies establish a basic understanding of the indole element of the HIV attachment inhibitor pharmacophore. 相似文献
5.
Kirk SR Andrade AL Melich K Jackson EP Cuellar E Karpen JW 《Bioorganic & medicinal chemistry letters》2011,21(21):6417-6419
A series of new tetracaine derivatives with substituents on the aromatic ring was prepared and evaluated for block of retinal rod cyclic nucleotide-gated (CNG) channels. Aromatic substitutions had little effect starting with the basic tetracaine scaffold, but electron-withdrawing substituents significantly improved the blocking potency of an octyl-tail derivative of tetracaine. In particular, halogen substitutions at either the 2- or 3-position on the ring resulted in compounds that were up to eight-fold more potent than the parent octyl-tail derivative and up to 50-fold more potent than tetracaine. 相似文献
6.
Zeng XF Li WW Fan HJ Wang XY Ji P Wang ZR Ma S Li LL Ma XF Yang SY 《Bioorganic & medicinal chemistry letters》2011,21(16):4742-4744
Development of fatty acid synthase (FAS) inhibitors has increasingly attracted much attention in recent years due to their potential therapeutic use in obesity and cancers. In this investigation, pharmacophore modeling based on the first crystal structure of human KS domain of FAS was carried out. The established pharmacophore model was taken as a 3D query for retrieving potent FAS inhibitors from the chemical database Specs. Docking study was further carried out to refine the obtained hit compounds. Finally, a total of 28 compounds were selected based on the ranking order and visual examination, which were first evaluated by a cell line-based assay. Seven compounds that have good inhibition activity against two FAS overexpressing cancer cell lines were further evaluated by an enzyme-based assay. One compound with a new chemical scaffold was found to have low micromolar inhibition potency against FAS, which has been subjected to further chemical structural modification. 相似文献
7.
Faten Sliman Mélina Blairvacq Emilie Durieu Laurent Meijer Jordi Rodrigo Didier Desmaële 《Bioorganic & medicinal chemistry letters》2010,20(9):2801-2805
Pim-1 kinase is a cytoplasmic serine/threonine kinase that controls programmed cell death by phosphorylating substrates that regulate both apotosis and cellular metabolism. A series of 2-styrylquinolines and quinoline-2-carboxamides has been identified as potent inhibitors of the Pim-1 kinase. The 8-hydroxy-quinoline 7-carboxylic acid moiety appeared to be a crucial pharmacophore for activity. Molecular modeling indicated that interaction of this scaffold with Asp186 and Lys67 residues within the ATP-binding pocket might be responsible for the kinase inhibitory potency. 相似文献
8.
Kazmierski WM Furfine E Gray-Nunez Y Spaltenstein A Wright L 《Bioorganic & medicinal chemistry letters》2004,14(22):5685-5687
We have developed synthetic approaches to novel analogues of 2-imidazolidinone scaffold 2, which was found to be an effective P1-P2 mimetic in HIV-1 protease inhibitor 4. This enabled a rapid synthesis of analogues of 4 and subsequently allowed us to evaluate and rationalize the SAR. Accordingly, trans relationship of P1 and P2 substituents in the P1-P2 mimetic, as found in a related 2-pyrrolidone-based scaffold 1, was found necessary for high potency against HIV-1 protease. Results of this study provided further rationale towards subsequent optimization of 2-pyrrolidone-based lead 3, which led us to potent and drug-like HIV-1 protease inhibitors described in a follow-on report (Bioorg. Med. Chem. Lett. 2004, 14, in press. ). 相似文献
9.
Mikhail Krasavin Alexey Lukin Nikolay Zhurilo Alexey Kovalenko Ihor Zahanich Sergey Zozulya 《Journal of enzyme inhibition and medicinal chemistry》2016,31(6):1404-1410
1,3,4-Thiadiazole was explored as a more polar, heterocyclic replacement for the phenyl ring in the 3-arylpropionic acid pharmacophore present in the majority of GPR40 agonists. Out of 13 compounds synthesized using a flexible, three-step protocol (involving no chromatographic purification), four compounds were confirmed to activate the target in micromolar concentration range. While the potency of the series should be subject of further optimization, the remarkable aqueous solubility and microsomal stability observed for the lead compound (8g) apparently attests to this new scaffold’s high promise in the GPR40 agonist field. 相似文献
10.
The allosteric effect on muscarinic acetylcholine M2 receptors of 11 bisquaternary salts of the Strychnos alkaloid caracurine V was determined. The effect was indicated by the concentration which retarded the rate of dissociation of the antagonist [3H]-N-methylscopolamine from porcine cardiac cholinoceptors by a factor of 2 (EC50). The most potent compounds carry allyl and propargyl substituents, respectively. Introduction of more bulky substituents (e.g., benzyl groups) resulted in a considerably reduced allosteric potency. The wide range of EC50 values (3 nM for R = allyl. 1750 nM for R = 2-naphthyl) suggests a sterically restricted binding pocket. Molecular modeling studies indicated that the caracurine V ring system satisfies the pharmacophore model for the allosteric interaction. 相似文献
11.
Schroeder GM Chen XT Williams DK Nirschl DS Cai ZW Wei D Tokarski JS An Y Sack J Chen Z Huynh T Vaccaro W Poss M Wautlet B Gullo-Brown J Kellar K Manne V Hunt JT Wong TW Lombardo LJ Fargnoli J Borzilleri RM 《Bioorganic & medicinal chemistry letters》2008,18(6):1945-1951
An amide library derived from the pyrrolo[2,1-f][1,2,4]triazine scaffold led to the identification of modest inhibitors of Met kinase activity. Introduction of polar side chains at C-6 of the pyrrolotriazine core provided significant improvements in in vitro potency. The amide moiety could be replaced with acylurea and malonamide substituents to give compounds with improved potency in the Met-driven GTL-16 human gastric carcinoma cell line. Acylurea pyrrolotriazines with substitution at C-5 demonstrated single digit nanomolar kinase activity. X-ray crystallography revealed that the C-5 substituted pyrrolotriazines bind to the Met kinase domain in an ATP-competitive manner. 相似文献
12.
Martin Tremblay Richard C. Bethell Michael G. Cordingley Patrick DeRoy Jianmin Duan Martin Duplessis Paul J. Edwards Anne-Marie Faucher Ted Halmos Clint A. James Cyrille Kuhn Jean-Éric Lacoste Louie Lamorte Steven R. LaPlante Éric Malenfant Joannie Minville Louis Morency Sébastien Morin Claudio F. Sturino 《Bioorganic & medicinal chemistry letters》2013,23(9):2775-2780
13.
Hu-Shan Zhang Dong-Zhi Feng Li Chen Ya-Qiu Long 《Bioorganic & medicinal chemistry letters》2010,20(7):2219-2223
By using functionality inversion approach, we identified a new scaffold containing (S)-α-phenyl-γ-amino butanamide as CCR5 antagonists derived from the 1,3-propanediamine carboxamide pharmacophore protocol. The (2S)-2-phenyl-4-(8-aza-bicyclo[3.2.1]octan-8-yl)-butanamide derivatives display significantly high potency to antagonize CCR5 receptor with nanomolar IC50 values. 相似文献
14.
Yongqi Deng Zhiwei Yang Gerald W. Shipps Sie-Mun Lo Robert West Joyce Hwa Shuqin Zheng Constance Farley Jean Lachowicz Margaret van Heek Alan S. Bass Dinesh P. Sinha Craig R. Mahon Mark E. Cartwright 《Bioorganic & medicinal chemistry letters》2013,23(3):791-796
Inhibitors based on a benzo-fused spirocyclic oxazepine scaffold were discovered for stearoyl-coenzyme A (CoA) desaturase 1 (SCD1) and subsequently optimized to potent compounds with favorable pharmacokinetic profiles and in vivo efficacy in reducing the desaturation index in a mouse model. Initial optimization revealed potency preferences for the oxazepine core and benzylic positions, while substituents on the piperidine portions were more tolerant and allowed for tuning of potency and PK properties. After preparation and testing of a range of functional groups on the piperidine nitrogen, three classes of analogs were identified with single digit nanomolar potency: glycine amides, heterocycle-linked amides, and thiazoles. Responding to concerns about target localization and potential mechanism-based side effects, an initial effort was also made to improve liver concentration in an available rat PK model. An advanced compound 17m with a 5-carboxy-2-thiazole substructure appended to the spirocyclic piperidine scaffold was developed which satisfied the in vitro and in vivo requirements for more detailed studies. 相似文献
15.
Boyer SJ Burke J Guo X Kirrane TM Snow RJ Zhang Y Sarko C Soleymanzadeh L Swinamer A Westbrook J Dicapua F Padyana A Cogan D Gao A Xiong Z Madwed JB Kashem M Kugler S O'Neill MM 《Bioorganic & medicinal chemistry letters》2012,22(1):733-737
A series of inhibitors for the 90 kDa ribosomal S6 kinase (RSK) based on an 1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxamide scaffold were identified through high throughput screening. An RSK crystal structure and exploratory SAR were used to define the series pharmacophore. Compounds with good cell potency, such as compounds 43, 44, and 55 were identified, and form the basis for subsequent kinase selectivity optimization. 相似文献
16.
Gopalsamy A Lim K Ellingboe JW Krishnamurthy G Orlowski M Feld B van Zeijl M Howe AY 《Bioorganic & medicinal chemistry letters》2004,14(16):4221-4224
A novel series of HCV NS5B RNA dependent RNA polymerase inhibitors containing a naphthalene carboxamide scaffold were identified by high throughput screening. Optimization of substituents by parallel synthesis and the iterative design towards understanding structure-activity relationship to improve potency are described. Tetra substituted naphthalene 31 displayed potent activity with IC(50) of 120 nM against HCV NS5B enzyme and was selective over a panel of polymerases. 相似文献
17.
Manuel Koller David A. Carcache David Orain Peter Ertl Dirk Behnke Sandrine Desrayaud Grit Laue Ivo Vranesic 《Bioorganic & medicinal chemistry letters》2012,22(20):6454-6459
1H-pyrrolo[2,3-c]pyridine-7-carboxamides constitute a new series of allosteric mGluR5 antagonists. Variation of the substituents attached to the heterocyclic scaffold allowed to improve the physico-chemical parameters for optimization of the aqueous solubility while retaining high in vitro potency. 相似文献
18.
Sampath-Kumar Anandan Zung N. Do Heather K. Webb Dinesh V. Patel Richard D. Gless 《Bioorganic & medicinal chemistry letters》2009,19(4):1066-1070
Inhibition of soluble epoxide hydrolase has been proposed as a promising new pharmaceutical target for diseases involving hypertension and vascular inflammation. The most potent sEH inhibitors reported to date contain a urea or amide moiety as the central or ‘primary’ pharmacophore. We evaluated replacing the urea pharmacophore with other functional groups such as thiourea, sulfonamide, sulfonylurea, aminomethylene amide, hydroxyamide, and ketoamide to identify novel and potent inhibitors. The hydroxyamide moiety was identified as a novel pharmacophore affording potency comparable to urea. 相似文献
19.
The 3-aryl-2-cyanoacrylamide scaffold was designed as core pharmacophore for inhibitors of the Dengue and West Nile virus serine proteases (NS2B-NS3). A total of 86 analogs was prepared to study the structure–activity relationships in detail. Thereby, it turned out that the electron density of the aryl moiety and the central double bond have a crucial influence on the activity of the compounds, whereas the influence of substituents of the amide residue is less relevant. The para-hydroxy substituted analog was found to be the most potent inhibitor in this series with a Ki-value of 35.7 μM at the Dengue and 44.6 μM at the West Nile virus protease. The aprotinin competition assay demonstrates a direct interaction of the inhibitor molecule with active centre of the Dengue virus protease. The target selectivity was studied in a counterscreen with thrombin and found to be 2.8:1 in favor of DEN protease and 2.3:1 in favor of WNV protease, respectively. 相似文献
20.
A series of novel 6,7-dihydro-5H-cyclopenta[d]pyrimidine derivatives was successfully designed, synthesized and evaluated as a new chemical scaffold with vascular endothelial growth factor receptor (VEGFR 2) inhibitory activity. Compounds 6c and 6b showed enzyme inhibition of 97% and 87% at 10 µM, respectively, and exhibited potent dose-related VEGFR 2 inhibition with IC50 values of 0.85 µM and 2.26 µM, respectively. The design of the 6,7-dihydro-5H-cyclopenta[d]pyrimidine scaffold was implemented via consecutive molecular modelling protocols prior to the synthesis and biological evaluation of the derivatives. First, sorafenib was docked in the binding site of VEGFR 2 to study its binding orientation and affinity, followed by the generation of a valid 3D QSAR pharmacophore model for use in the virtual screening of different 3D databases. Structures with promising pharmacophore-based virtual screening results were refined using molecular docking studies in the binding site of VEGFR 2. A novel scaffold was designed by incorporating the results of the pharmacophore model generation and molecular docking studies. The new scaffold showed hydrophobic interactions with the kinase front pocket that may be attributed to increasing residence time in VEGFR 2, which is a key success factor for ligand optimization in drug discovery. Different derivatives of the novel scaffold were validated using docking studies and pharmacophore mapping, where they exhibited promising results as VEGFR 2 inhibitors to be synthesized and biologically evaluated. 6,7-dihydro-5H-cyclopenta[d]pyrimidine is a new scaffold that can be further optimized for the synthesis of promising VEGFR 2 inhibitors. 相似文献