共查询到20条相似文献,搜索用时 15 毫秒
1.
Sonja Nordhoff Silvia Cerezo-Gálvez Holger Deppe Oliver Hill Meritxell López-Canet Christian Rummey Meinolf Thiemann Victor G. Matassa Paul J. Edwards Achim Feurer 《Bioorganic & medicinal chemistry letters》2009,19(15):4201-4203
Modifications of DPP-4 inhibitor 5, that was discovered by structure based design, are described and structure–activity relationships discussed. With analogue 7k one of the most potent non-covalent inhibitors of DPP-4 reported to date (IC50 = 0.38 nM) was discovered. X-ray structure of inhibitor 7k bound to DPP-4 revealed a hydrogen bonding interaction with Q553. First successful efforts in balancing overall properties, as demonstrated by improved metabolic stability, highlight the potential of this series. 相似文献
2.
Yan-Ke Jiang 《Journal of molecular modeling》2010,16(7):1239-1249
Three-dimensional quantitative structure-activity relationship (3D-QSAR) and molecular docking studies were carried out to
explore the binding of 73 inhibitors to dipeptidyl peptidase IV (DPP-IV), and to construct highly predictive 3D-QSAR models
using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The negative
logarithm of IC50 (pIC50) was used as the biological activity in the 3D-QSAR study. The CoMFA model was developed by steric and electrostatic field
methods, and leave-one-out cross-validated partial least squares analysis yielded a cross-validated value (rcv2 {\hbox{r}}_{{\rm{cv}}}^{\rm{2}} ) of 0.759. Three CoMSIA models developed by different combinations of steric, electrostatic, hydrophobic and hydrogen-bond
fields yielded significant rcv2 {\hbox{r}}_{{\rm{cv}}}^{\rm{2}} values of 0.750, 0.708 and 0.694, respectively. The CoMFA and CoMSIA models were validated by a structurally diversified
test set of 18 compounds. All of the test compounds were predicted accurately using these models. The mean and standard deviation
of prediction errors were within 0.33 and 0.26 for all models. Analysis of CoMFA and CoMSIA contour maps helped identify the
structural requirements of inhibitors, with implications for the design of the next generation of DPP-IV inhibitors for the
treatment of type 2 diabetes. 相似文献
3.
《Bioorganic & medicinal chemistry》2014,22(13):3441-3448
A series of 6-chloro-3-oxindole derivatives 1–25 were synthesized in high yields by the reaction of 6-chlorooxindole with different aromatic aldehydes in the presence of piperidine. All the synthesized compounds were isolated with E configuration. The structures were confirmed using spectroscopic techniques, including 1H NMR and EIMS. These compounds showed varying degree of yeast α-glucosidase inhibition and seven were found as potent inhibitors of the enzyme. Compounds 2, 3, 4, 5, 6, 23, and 25 exhibited IC50 values 2.71 ± 0.007, 11.41 ± 0.005, 37.93 ± 0.002, 15.19 ± 0.004, 24.71 ± 0.007, 17.33 ± 0.001, and 14.2 ± 0.002 μM, respectively, as compared to standard acarbose (IC50, 38.25 ± 0.12 μM). Docking studies helped to find interactions between the enzyme and the active compounds. As a result of this study, oxindoles have been discovered as a new class of α-glucosidase inhibitors which have not been reported earlier. 相似文献
4.
Wang T Block MA Cowen S Davies AM Devereaux E Gingipalli L Johannes J Larsen NA Su Q Tucker JA Whitston D Wu J Zhang HJ Zinda M Chuaqui C 《Bioorganic & medicinal chemistry letters》2012,22(5):2063-2069
The design, synthesis and biological evaluation of a series of azabenzimidazole derivatives as TBK1/IKKε kinase inhibitors are described. Starting from a lead compound 1a, iterative design and SAR exploitation of the scaffold led to analogues with nM enzyme potencies against TBK1/IKKε. These compounds also exhibited excellent cellular activity against TBK1. Further structure-based design to improve selectivity over CDK2 and Aurora B resulted in compounds such as 5b-e. These probe compounds will facilitate study of the complex cancer biology of TBK1 and IKKε. 相似文献
5.
《Bioorganic & medicinal chemistry letters》2020,30(20):127489
Twenty novel 1,2,3-triazole noscapine derivatives were synthesized starting from noscapine by consecutive N-demethylation, reduction of lactone ring, N-propargylation and Huisgen 1,3-dipolar cycloaddition reaction. In order to select the most promising molecules to subject to further biophysical and biological evaluation, a molecular docking analysis round was performed using noscapine as reference compound. The molecules featuring docking predicted binding affinity better than that of noscapine were then subjected to MTT assay against MCF7 cell line. The obtained results disclosed that all the selected triazole derivatives exhibited a remarkably lower cell viability compared to noscapine in the range of 20 μM in 48 h. In an attempt to correlate the biological activity with the ability to bind tubulin, the surface plasmon resonance (SPR) assay was employed. Compounds 8a, 8h, 9c, 9f and 9j were able to bind tubulin with affinity constant values in the nanomolar range and higher if compared to noscapine. Integrating computational predictions and experimental evaluation, two promising compounds (8h and 9c) were identified, whose relevant cytotoxicity was supposed to be correlated with tubulin binding affinity. These findings shed lights onto structural modifications of noscapine toward the identification of more potent cytotoxic agents targeting tubulin. 相似文献
6.
Luckhurst CA Stein LA Furber M Webb N Ratcliffe MJ Allenby G Botterell S Tomlinson W Martin B Walding A 《Bioorganic & medicinal chemistry letters》2011,21(1):492-496
Small molecule isoindoline and tetrahydroisoquinoline derivatives have been identified as selective agonists of human peroxisome proliferator-activated receptor δ (PPARδ. Compound 18 demonstrated efficacy in a biomarker for increased fatty acid oxidation, with upregulation of pyruvate dehydrogenase kinase, isozyme 4 (PDK4) in human primary myotubes. 相似文献
7.
Shan Z Peng M Fan H Lu Q Lu P Zhao C Chen Y 《Bioorganic & medicinal chemistry letters》2011,21(6):1731-1735
A series of novel [1,2,3]-triazolopiperidine derivatives 5a-5y were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4) for the treatment of type 2 diabetes, most of the compounds exhibited excellent in vitro potency (IC50 <50 nM) against DPP-4. Among these, compound 5d with potent in vitro activity against DPP-4 and good pharmacokinetic profiles exhibited pronounced in vivo efficacy in an oral glucose tolerance test (OGTT) in ICR mice. On the base of these properties, compound 5d was selected as a potential new candidate for the treatment of type 2 diabetes. 相似文献
8.
Tatsuya Maruyama Kenichi Onda Masahiko Hayakawa Norio Seki Takumi Takahashi Hiroyuki Moritomo Takayuki Suzuki Tetsuo Matsui Toshiyuki Takasu Itsuro Nagase Mitsuaki Ohta 《Bioorganic & medicinal chemistry》2009,17(9):3283-3294
In the search for potent and selective human β3-adrenergic receptor (AR) agonists as potential drugs for the treatment of obesity and noninsulin-dependent (type II) diabetes, a novel series of phenoxypropanolamine derivatives containing acetanilides were prepared and their biological activities were evaluated at the human β3-, β2-, and β1-ARs. Several of the analogues (21a, 21b, and 27a) exhibited potent agonistic activity at the β3-AR. Among the compounds described herein, the N-methyl-1-benzylimidazol-2-ylacetanilide derivative (21b) was found to be the most potent and selective β3-AR agonist, with an EC50 value of 0.28 μM and no agonistic activity for either the β1- or β2-AR. In addition, 21b showed significant hypoglycemic activity in a rodent diabetic model. 相似文献
9.
《Bioorganic & medicinal chemistry letters》2020,30(1):126715
A high-throughput screening (HTS) campaign identified a class of heteroaryl piperazines with excellent baseline affinity and selectivity for phosphoinositide 3-kinase δ (PI3Kδ) over closely related isoforms. Rapid evaluation and optimization of structure-activity relationships (SAR) for this class, leveraging the modular nature of this scaffold, facilitated development of this hit class into a series of potent and selective inhibitors of PI3Kδ. This effort culminated in the identification of 29, which displayed excellent potency in enzyme and cell-based assays, as well as favorable pharmacokinetic and off-target profiles. 相似文献
10.
Sonja Nordhoff Meritxell López-Canet Barbara Hoffmann-Enger Stephan Bulat Silvia Cerezo-Gálvez Oliver Hill Claudia Rosenbaum Christian Rummey Meinolf Thiemann Victor G. Matassa Paul J. Edwards Achim Feurer 《Bioorganic & medicinal chemistry letters》2009,19(16):4818-4823
A series of highly potent and selective inhibitors of DPP-4 was optimized for ADMET properties. The effort resulted in the discovery of inhibitor 1g, that exhibits excellent efficacy in an oral glucose tolerance test and an attractive pharmacokinetic profile. 相似文献
11.
Motoshima K Sugita K Hashimoto Y Ishikawa M 《Bioorganic & medicinal chemistry letters》2011,21(10):3041-3045
Novel dipeptidyl peptidase IV (DPP-IV) inhibitors with a phenethylphenylphthalimide skeleton were prepared based on α-glucosidase inhibitors and liver X receptor (LXR) antagonists derived from thalidomide. Representative compounds showed non-competitive inhibition of DPP-IV and 28a exhibited 10-fold selectivity for DPP-IV over DPP-8. Compound 28a is the first non-competitive, selective DPP-IV inhibitor. 相似文献
12.
Ina Terstiege Matthew Perry Jens Petersen Christian Tyrchan Tor Svensson Helena Lindmark Linda Öster 《Bioorganic & medicinal chemistry letters》2017,27(3):679-687
A novel class of potent PI3Kδ inhibitors with >1000-fold selectivity against other class I PI3K isoforms is described. Optimization of the substituents on a triazole aminopyrazine scaffold, emerging from an in-house PI3Kα program, turned moderately selective PI3Kδ compounds into highly potent and selective PI3Kδ inhibitors. These efforts resulted in a series of aminopyrazines with PI3Kδ IC50 ? 1 nM in the enzyme assay, some of the most selective PI3Kδ inhibitors published to date, with a cell potency in a JeKo-cell assay of 20–120 nM. 相似文献
13.
Anna A. Hovhannisyan The Hien Pham Dominique Bouvier Xiao Tan SiAmmar Touhar Gevorg G. Mkryan Ashot M. Dallakyan Chahrazade El Amri Gagik S. Melikyan Michèle Reboud-Ravaux Michelle Bouvier-Durand 《Bioorganic & medicinal chemistry letters》2017,27(23):5172-5178
New series of thiophene-containing phenoxypropanolamines were synthesized and evaluated for their potency to inhibit the three proteolytic activities of the mammalian 20S proteasome. Noticeable inhibition of both ChT-L and PA activities was obtained with three compounds: one with unsubstituted phenoxypropanolamine group (7) and the two others with a p-Cl-substituted group (4 and 9). For three other compounds (3, 8 and 10), ChT-L activity alone was significantly inhibited. In silico docking performed on the β5 and β1 subunits bearing the respective ChT-L and PA catalytic sites showed features common to poses associated with active compounds. These features may constitute a selectivity criterion for structure-guided inhibitor design. 相似文献
14.
H Song YS Lee EJ Roh JH Seo KS Oh BH Lee H Han KJ Shin 《Bioorganic & medicinal chemistry letters》2012,22(17):5668-5674
Regulation of NF-κB activation through the inhibition of IKKβ has been identified as a promising target for the treatment of inflammatory and autoimmune disease such as rheumatoid arthritis. In order to develop novel IKKβ inhibitors, we performed high throughput screening toward around 8000 library compounds, and identified a hit compound containing rhodanine moiety. We modified the structure of hit compound to obtain potent and selective IKKβ inhibitors. Throughout hit-to-lead studies, we have discovered optimized compounds which possess blocking effect toward NF-κB activation and TNFα production in cell as well as inhibition activity against IKKβ. Among them, compound 3q showed the potent inhibitory activity against IKKβ, and excellent selectivity over other kinases such as p38α, p38β, JNK1, JNK2, and JNK3 as well as IKKα. 相似文献
15.
Muhammad Taha Syahrul Imran Munther Alomari Fazal Rahim Abdul Wadood Ashik Mosaddik Nizam Uddin Mohammed Gollapalli Mohammed A. Alqahtani Yasser A. Bamarouf 《Bioorganic & medicinal chemistry》2019,27(14):3145-3155
A new series of oxadiazole with thiadiazole moiety (6–27) were synthesized, characterized by different spectroscopic techniques and evaluated for β-glucuronidase inhibitory potential. Sixteen analogs such as 6, 7, 8, 9, 10, 12, 13, 14, 17, 18, 20, 23, 24, 25, 26 and 27 showed IC50 values in the range of 0.96 ± 0.01 to 46.46 ± 1.10 μM, and hence were found to have excellent inhibitory potential in comparison to standard d-saccharic acid 1,4-lactone (IC50 = 48.4 ± 1.25 μM). Two analogs such as 16 and 19 showed moderate inhibitory potential while analogs 11, 15, 21 and 22 were found inactive. Our study identifies new series of potent β-glucuronidase inhibitors for further investigation. Structure activity relationships were established for all compounds which showed that the activity is varied due to different substituents on benzene ring. The interaction of the compounds with enzyme active site were confirmed with the help of docking studies, which reveals that the electron withdrawing group and hydroxy group make the molecules more favorable for enzyme inhibition. 相似文献
16.
Jérôme Amaudrut Maria A. Argiriadi Martine Barth Eric C. Breinlinger Didier Bressac Pierre Broqua David J. Calderwood Mohamed Chatar Kevin P. Cusack Stephen B. Gauld Sébastien Jacquet Rajesh V. Kamath Michael E. Kort Valérie Lepais Jean-Michel Luccarini Philippe Masson Christian Montalbetti Laurent Mounier Craig D. Wallace 《Bioorganic & medicinal chemistry letters》2019,29(14):1799-1806
A high-throughput screen against Inventiva’s compound library using a Gal4/RORγ-LBD luciferase reporter gene assay led to the discovery of a new series of quinoline sulphonamides as RORγ inhibitors, eventually giving rise to a lead compound having an interesting in vivo profile after oral administration. This lead was evaluated in a target engagement model in mouse, where it reduced IL-17 cytokine production after immune challenge. It also proved to be active in a multiple sclerosis model (EAE) where it reduced the disease score. The synthesis, structure activity relationship (SAR) and biological activity of these derivatives is described herein. 相似文献
17.
Toshihiro Hamajima Fumie Takahashi Koji Kato Koichiro Mukoyoshi Kousei Yoshihara Susumu Yamaki Yukihito Sugano Ayako Moritomo Kaoru Yamagami Koji Yokoo Hidehiko Fukahori 《Bioorganic & medicinal chemistry》2018,26(9):2410-2419
Phosphatidylinositol-3-kinase (PI3K)δ inhibition is one of the most attractive approaches to the treatment of autoimmune diseases and leukocyte malignancies. Through the exploration of pyrazolopyridine derivatives as potential PI3Kδ inhibitors, compound 12a was identified as a potent PI3Kδ inhibitor but suffered from poor oral exposure in mice. With a modified amide linkage group, compound 15a was developed as an orally available PI3Kδ inhibitor with reduced selectivity against other PI3Ks. To improve the trade-off between selectivity and PK profile, structure–activity relationship (SAR) studies of terminal substituents on the pyrolidine ring were conducted. As a result, we developed potent PI3Kδ inhibitors with good oral availability. In particular, the representative compound 15j showed excellent selectivity for PI3Kδ over other PI3Ks with good oral exposure in mice. 相似文献
18.
Das J Moquin RV Dyckman AJ Li T Pitt S Zhang R Shen DR McIntyre KW Gillooly K Doweyko AM Newitt JA Sack JS Zhang H Kiefer SE Kish K McKinnon M Barrish JC Dodd JH Schieven GL Leftheris K 《Bioorganic & medicinal chemistry letters》2010,20(23):6886-6889
The synthesis and structure-activity relationships (SAR) of p38α MAP kinase inhibitors based on a 5-amino-pyrazole scaffold are described. These studies led to the identification of compound 2j as a potent and selective inhibitor of p38α MAP kinase with excellent cellular potency toward the inhibition of TNFα production. Compound 2j was highly efficacious in vivo in inhibiting TNFα production in an acute murine model of TNFα production. X-ray co-crystallography of a 5-amino-pyrazole analog 2f bound to unphosphorylated p38α is also disclosed. 相似文献
19.
Aiguadé J Balagué C Carranco I Caturla F Domínguez M Eastwood P Esteve C González J Lumeras W Orellana A Preciado S Roca R Vidal L Vidal B 《Bioorganic & medicinal chemistry letters》2012,22(10):3431-3436
A new class of p38α inhibitors based on a biaryl-triazolopyridine scaffold was investigated. X-ray crystallographic data of the initial lead compound cocrystallised with p38α was crucial in order to uncover a unique binding mode of the inhibitor to the hinge region via a pair of water molecules. Synthesis and SAR was directed towards the improvement of binding affinity, as well as ADME properties for this new class of p38α inhibitors and ultimately afforded compounds showing good in vivo efficacy. 相似文献
20.
Nadim S. Shaikh Jitesh P. Iyer Yogesh S. Munot Partha P. Mukhopadhyay Amol A. Raje Ranganayaki Nagaraj Vijay Jamdar Ravindra Gavhane Mahendra Lohote Prasad Sherkar Madhu Bala Rajkanth Petla Ashwinkumar Meru Dhananjay Umrani Sreekanth Rouduri Sachin Joshi Satyanarayan Reddy Vishwottam Kandikere Kasim A. Mookhtiar 《Bioorganic & medicinal chemistry letters》2019,29(16):2208-2217
Targeting nuclear receptor RORγ is recognized to be beneficial in multiple autoimmune disorders. We disclosed new indole analogues as potent RORγ inverse agonists. RO-2 as one of the potent and orally bioavailable compounds was evaluated in various models of autoimmune disorder. It showed potent suppression of downstream markers of RORγt activity in murine and human primary cells, ex vivo PD assay and in multiple animal models of autoimmune diseases. The results indicate the potential of these indole analogues as orally bioavailable small molecule inverse agonists of RORγt, efficacious in various Th17 driven models of autoimmune disorders. 相似文献