共查询到20条相似文献,搜索用时 15 毫秒
1.
Phosphatidylinositol-3-kinase beta (PI3Kβ) is an important therapeutic target in arterial thrombosis and special types of cancer. In this study, a new series of aminopyridine-based PI3Kβ selective inhibitors have been developed by the structure-based design strategy. When incorporated with the phenyl ring on sulfonamide moiety, aminopyrimidine analogs showed good potency on PI3Kβ and selectivity over PI3Kα. Intriguingly, replacement of phenyl group on sulfonamide with naphthyl group enhanced selectivity over PI3Kα while retaining submicromolar PI3Kβ potency. Molecular modeling suggests that increased PI3Kβ specificity is caused by the interaction with salt bridge (Lys782-Asp923) and Asp862 that creat a unique pocket in PI3Kβ. These results clearly provide useful insight in the design of new PI3Kβ inhibitors with high potency and selectivity. 相似文献
2.
Yusuke Oka Tetsuya Yabuuchi Yasuyuki Fujii Hidenori Ohtake Shunichi Wakahara Kayo Matsumoto Mayumi Endo Yunoshin Tamura Yoshinori Sekiguchi 《Bioorganic & medicinal chemistry letters》2012,22(24):7534-7538
A novel series of 2-aminothiazole-oxazoles was designed and synthesized as part of efforts to develop potent phosphoinositide 3-kinase γ (PI3Kγ) inhibitors. The modification of a high-throughput screening hit, compound 1, resulted in the identification of compounds 10 and 15, which displayed potent inhibitory activities in enzyme-based and cell-based assays. 相似文献
3.
Bernard Barlaam Sabina Cosulich Martina Fitzek Hervé Germain Stephen Green Lyndsey L. Hanson Craig S. Harris Urs Hancox Kevin Hudson Christine Lambert-van der Brempt Maryannick Lamorlette Françoise Magnien Gilles Ouvry Ken Page Linette Ruston Lara Ward Bénédicte Delouvrié 《Bioorganic & medicinal chemistry letters》2017,27(13):3030-3035
We report the discovery of a novel aminopyrazine series of PI3Kα inhibitors, designed by hybridizing two known scaffolds of PI3K inhibitors. We describe the progress achieved from the first compounds plagued with poor general kinase selectivity to compounds showing high selectivity for PI3Kα over PI3Kβ and excellent general kinase selectivity. This effort culminated with the identification of compound 5 displaying high potency and selectivity, and suitable physiochemical and pharmacokinetic properties for oral administration. In vivo, compound 5 showed good inhibition of tumour growth (86% tumour growth inhibition at 50 mg/kg twice daily orally) in the MCF7 xenograft model in mice. 相似文献
4.
Steven T. Staben Chudi Ndubaku Nicole Blaquiere Marcia Belvin Richard J. Bull Danette Dudley Kyle Edgar Daniel Gray Robert Heald Timothy P. Heffron Graham E. Jones Mark Jones Aleks Kolesnikov Leslie Lee John Lesnick Cristina Lewis Jeremy Murray Neville J. McLean Ping Wu 《Bioorganic & medicinal chemistry letters》2013,23(9):2606-2613
A series of suitable five-membered heterocyclic alternatives to thiophenes within a thienobenzoxepin class of PI3-kinase (PI3K) inhibitors was discovered. Specific thiazolobenzoxepin 8-substitution was identified that increased selectivity over PI3Kβ. PI3Kβ-sparing compound 27 (PI3Kβ Ki,app/PI3Kα Ki,app = 57) demonstrated dose-dependent knockdown of pAKT, pPRAS40 and pS6RP in vivo as well as differential effects in an in vitro proliferation cell line screen compared to pan PI3K inhibitor GDC-0941. A new structure-based hypothesis for reducing inhibition of the PI3K β isoform while maintaining activity against α, δ and γ isoforms is presented. 相似文献
5.
Minhang Xin Weiming Duan Yifan Feng Yuan-Yuan Hei Hao Zhang Ying Shen Hong-Yi Zhao Shuai Mao San-Qi Zhang 《Bioorganic & medicinal chemistry》2018,26(8):2028-2040
In this study, a novel series of 6-aryl substituted 4-pyrrolidineaminoquinazoline derivatives were designed and evaluated as potent PI3Kδ inhibitors. The preliminary SAR was established, and compounds 12d, 20a and 20c displayed leading potent PI3Kδ inhibition, with IC50 values of 4.5, 2.7 and 3.1?nM, respectively, that were comparable to idelalisib (IC50?=?2.7?nM). Moreover, these three compounds showed favorable PI3Kδ isoform selectivity over PI3Kα, PI3Kβ, and PI3Kγ, and showed distinct anti-proliferation profiles against four human B cell lines of Ramos, Raji, RPMI-8226 and SU-DHL-6. In addition, molecular docking simulation showed that several key hydrogen bonding interactions were formed for compounds 12d, 20a and 20c in the PI3Kδ pocket, which might explain their potent PI3Kδ inhibition. These results indicate the 6-aryl substituted 4-pyrrolidineaminoquinazolines were potent PI3Kδ inhibitors. 相似文献
6.
Ellard K Sunose M Bell K Ramsden N Bergamini G Neubauer G 《Bioorganic & medicinal chemistry letters》2012,22(14):4546-4549
Dual PI3Kγ/δ inhibitors have recently been shown to be suitable targets for inflammatory and respiratory diseases. In a recent study we described the discovery of selective PI3Kγ inhibitors based on a triazolopyridine scaffold. Herein, we describe the elaboration of this structural class into dual PI3Kγ/δ inhibitors with excellent selectivity over the other PI3K isoforms and the general kinome. Structural optimization led to the identification of two derivatives which showed significant efficacy in an acute model of lung inflammation. 相似文献
7.
Minhang Xin Weiming Duan Yifan Feng Yuan-Yuan Hei Hao Zhang Ying Shen 《Journal of enzyme inhibition and medicinal chemistry》2018,33(1):651-656
Phosphoinositide 3-kinase Delta (PI3Kδ) plays a key role in B-cell signal transduction and inhibition of PI3Kδ was confirmed to have clinical benefit in certain types of activation of B-cell malignancies. Herein, we reported a novel series of 4-pyrrolidineoxy or 4-piperidineamino substituted quinazolines, showing potent PI3Kδ inhibitory activities. Among these compounds, 12d, 14b and 14c demonstrated higher potency against PI3Kδ with the half maximal inhibitory concentration (IC50) values of 4.5, 3.0, and 3.9?nM, respectively, which were comparable to idelalisib (IC50?=?2.7?nM). The further PI3K isoforms selectivity evaluation showed that compounds 12d, 14b and 14c have excellent PI3Kδ selectivity over PI3Kα, PI3Kβ, and PI3Kγ. Moreover, compounds 12d, 14b and 14c also displayed different anti-proliferative profiles against a panel of four human B cell lines including Ramos, Raji, RPMI-8226, and SU-DHL-6. The molecular docking simulation indicated several key hydrogen bonding interactions were formed. This study suggests the introduction of pyrrolidineoxy or piperidineamino groups into the 4-position of quinazoline leads to new potent and selective PI3Kδ inhibitors. 相似文献
8.
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
9.
Yoshihiro Usui Fumiaki Uehara Shinsuke Hiki Kazutoshi Watanabe Hiroshi Tanaka Aya Shouda Satoshi Yokoshima Keiichi Aritomo Takashi Adachi Kenji Fukunaga Shinji Sunada Mika Nabeno Ken-Ichi Saito Jun-ichi Eguchi Keiji Yamagami Shouichi Asano Shinji Tanaka Satoshi Yuki Takashi Horikawa 《Bioorganic & medicinal chemistry letters》2017,27(16):3726-3732
We herein describe the results of further evolution of glycogen synthase kinase (GSK)-3β inhibitors from our promising compounds containing a 2-phenylmorpholine moiety. Transformation of the morpholine moiety into a piperazine moiety resulted in potent GSK-3β inhibitors. SAR studies focused on the phenyl moiety revealed that a 4-fluoro-2-methoxy group afforded potent inhibitory activity toward GSK-3β. Based on docking studies, new hydrogen bonding between the nitrogen atom of the piperazine moiety and the oxygen atom of the main chain of Gln185 has been indicated, which may contribute to increased activity compared with that of the corresponding phenylmorpholine analogues. Effect of the stereochemistry of the phenylpiperazine moiety is also discussed. 相似文献
10.
Guangming Chen Hongyu Ren Anthony Turpoff Alexander Arefolov Richard Wilde James Takasugi Atiyya Khan Neil Almstead Zhengxian Gu Takashi Komatsu Connie Freund Jamie Breslin Joseph Colacino Jean Hedrick Marla Weetall Gary M. Karp 《Bioorganic & medicinal chemistry letters》2013,23(13):3942-3946
A series of novel 2-phenylindole analogs were synthesized and evaluated for activity in subgenomic HCV replicon inhibition assays. Several compounds containing small alkyl sulfonamides on the phenyl ring exhibiting submicromolar EC50 values against the genotype 1b replicon were identified. Among these, compound 25d potently inhibited the 1b replicon (EC50 = 0.17 μM) with 147-fold selectivity with respect to cytotoxicity. Compound 25d was stable in the presence of human liver microsomes and had a good pharmacokinetic profile in rats with an IV half-life of 4.3 h and oral bioavailability (F) of 58%. 相似文献
11.
Toshiyuki Kohara Kazuki Nakayama Kazutoshi Watanabe Shin-ichi Kusaka Daiki Sakai Hiroshi Tanaka Kenji Fukunaga Shinji Sunada Mika Nabeno Ken-Ichi Saito Jun-ichi Eguchi Akiko Mori Shinji Tanaka Tomoko Bessho Keiko Takiguchi-Hayashi Takashi Horikawa 《Bioorganic & medicinal chemistry letters》2017,27(16):3733-3738
We herein describe the results of further evolution of glycogen synthase kinase (GSK)-3β inhibitors from our promising compounds containing a 3-methylmorpholine moiety. Transformation of the morpholine moiety into a piperazine moiety resulted in potent GSK-3β inhibitors. SAR studies focused on the nitrogen atom of the piperazine moiety revealed that a phenyl group afforded potent inhibitory activity toward GSK-3β. Docking studies indicated that the phenyl group on the piperazine nitrogen atom and the methyl group on the piperazine make cation-π and CH-π interactions with GSK-3β respectively. 4-Methoxyphenyl analogue 29 showed most potent inhibitory activity toward GSK-3β with good in vitro and in vivo pharmacokinetic profiles, and 29 demonstrated a significant decrease in tau phosphorylation after oral administration in mice. 相似文献
12.
《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
13.
Kendall JD O'Connor PD Marshall AJ Frédérick R Marshall ES Lill CL Lee WJ Kolekar S Chao M Malik A Yu S Chaussade C Buchanan C Rewcastle GW Baguley BC Flanagan JU Jamieson SM Denny WA Shepherd PR 《Bioorganic & medicinal chemistry》2012,20(1):69-85
We have made a novel series of pyrazolo[1,5-a]pyridines as PI3 kinase inhibitors, and demonstrated their selectivity for the p110α isoform over the other Class Ia PI3 kinases. We investigated the SAR around the pyrazolo[1,5-a]pyridine ring system, and found compound 5x to be a particularly potent example (p110α IC(50) 0.9nM). This compound inhibits cell proliferation and phosphorylation of Akt/PKB, a downstream marker of PI3 kinase activity, and showed in vivo activity in an HCT-116 human xenograft model. 相似文献
14.
Pharmacophore modeling studies were undertaken for a series of compounds belonging several groups of phosphoinositide 3-kinase
(PI3K) p110α inhibitors: 4-morpholino-2-phenylquinazolines derivatives, pyrido[3′,2′:4,5]furo-[3,2-d]pyrimidine derivatives,
imidazo[1,2-a]pyridine derivatives, sulfonylhydrazone substituted imidazo[1,2-a]pyridines, and LY294002. A five-point pharmacophore
with three hydrogen bond acceptors (A), one hydrophobic group (H), and one aromatic ring (R) as pharmacophore features was
developed. The pharmacophore hypothesis yielded a statistically significant 3D-QSAR model, with a correlation coefficient
of R
2 = 0.95 for training set compounds. The model generated showed excellent predictive power, with a correlation coefficient
of Q
2 = 0.88 and r
pret2 = 0.95 for a test set of 14 compounds. Furthermore, the structure–activity relationships of PI3K p110α inhibitors were elucidated
and the activity differences between them discussed. Docking studies were also carried out wherein active and inactive compounds
were docked into the active site of the PI3K p110α crystal structure to analyze PI3K p110α–inhibitor interactions. The results
provide insights that will aid optimization of these classes of PI3K p110α inhibitors for better activity, and may prove helpful
for further lead optimization and virtual screening. 相似文献
15.
Yang Gao Peng Zhang Anfeng Cui De-Yong Ye Meng Xiang Yong Chu 《Bioorganic & medicinal chemistry》2018,26(20):5479-5493
Glycogen synthase kinase-3β (GSK-3β) has been identified to promote inflammation and its inhibitors have also been proven to treat some inflammatory mediated diseases in animal models. Non-ATP competitive inhibitors inherently have better therapeutical value due to their higher specificity than ATP competitive ones. In this paper, we designed and synthesized a series of new BTZ derivatives as non-ATP competitive GSK-3β inhibitors. Kinetic analysis revealed two typical compounds 6j and 3j showed the different non-ATP competitive mechanism of substrate competition or allosteric modulation to GSK-3β, respectively. As expected, the two compounds showed good specificity in a panel test of 16 protein kinases, even to the closest enzymes, like CDK-1/cyclin B and CK-II. The in vivo results proved that both compounds can greatly attenuate the LPS-induced acute lung injury (ALI) and diminish inflammation response in mice by inhibiting the mRNA expression of IL-1β and IL-6. Western blot analysis demonstrated that they negatively regulated GSK-3β, and the mechanism of the observed beneficial effects of the inhibitors may involve both the increased phosphorylation of the Ser9 residue on GSK-3β and protein expression of Sirtuin 1 (SIRT1). The results support that such novel BTZ compounds have a protective role in LPS-induced ALI, and might be attractive candidates for further development of inflammation pharmacotherapy, which greatly thanks to their inherently high selectivities by the non-ATP competitive mode of action. Finally, we proposed suggesting binding modes by Docking study to well explain the impacts of compounds on the target site. 相似文献
16.
M.V. Ramana Reddy Venkat R. Pallela Stephen C. Cosenza Muralidhar R. Mallireddigari Revathi Patti Marie Bonagura May Truongcao Balaiah Akula Shashidhar S. Jatiani E. Premkumar Reddy 《Bioorganic & medicinal chemistry》2010,18(6):2317-2326
Novel (E)-α-benzylthio chalcones are reported with preliminary in vitro activity data indicating that several of them are potent inhibitors (comparable to imatinib, the reference compound) of BCR-ABL phosphorylation in leukemic K562 cells, known to express high levels of BCR-ABL. The ability of such compounds to significantly inhibit K562 cell proliferation suggests that this scaffold could be a promising lead for the development of anticancer agents that are able to block BCR-ABL phosphorylation in leukemic cells. 相似文献
17.
β-ketoacyl-acyl carrier protein synthase III (FabH) catalyzes the initial step of fatty acid biosynthesis via a type II fatty acid synthase in most bacteria. The important role of this essential enzyme combined with its unique structural features and ubiquitous occurrence in bacteria has made it an attractive new target for the development of new FabH inhibitors. We first used a structure-based approach to develop 24 new vinylogous carbamates (4a-15a, 4b-15b) that target FabH for the development of new antibiotics in this paper. Potent FabH inhibitory and selective anti- Gram-negative bacteria activities were observed in most of these vinylogous carbamates. Especially, compound 6a and 7a showed the most potent FabH inhibitory activity with IC?? of 2.6 and 3.3 μM, respectively. Docking simulation was performed to position compound 6a into the Escherichia coli FabH active site and the possible binding conformation of compounds has been proposed. The biological data and molecular docking indicated that compounds 6a and 7a were potent inhibitors of E. coli FabH as antibiotics deserving further research. 相似文献
18.
Xiaokang Li Yahui Huang Junfei Cheng Lingling Zhang Fei Mao Jin Zhu Chunquan Sheng Jian Li 《Bioorganic & medicinal chemistry》2018,26(15):4375-4381
Due to the complex biological pathways involved in rheumatoid arthritis, discovery of multi-targeting small molecules provides an effective strategy to achieve better efficacy and lower toxicity. Herein the first Syk/PDGFR-α/c-Kit inhibitors were designed and evaluated. Dihydrofuropyrimidine derivative 13 showed potent inhibitory activity against the three targets. Importantly, compound 13 exhibited good cellular efficacy against fibroblast-like synoviocytes (IC50?=?3.21?μM) and mouse bone marrow-derived mast cells (IC50?=?2.03?μM) and significantly decreased the secretion of inflammatory cytokines. Thus, Syk/PDGFR-α/c-Kit triple inhibitor 13 represented a promising lead compound for the treatment of RA. 相似文献
19.
《Bioorganic & medicinal chemistry》2014,22(2):692-702
Novel series of N-(5-(arylcarbonyl)thiazol-2-yl)amides and N-(5-(arylcarbonyl)thiophen-2-yl)amides were discovered as potent retinoic acid receptor-related orphan receptor-gamma-t (RORγt) inhibitors. SAR studies of the RORγt HTS hit 6a led to identification of thiazole ketone amide 8h and thiophene ketone amide 9g with high binding affinity and inhibitory activity of Th17 cell differentiation. Compound 8h showed in vivo efficacy in both mouse experimental autoimmune encephalomyelitis (EAE) and collagen induced arthritis (CIA) models via oral administration. 相似文献
20.
Lan-Ying Qin Zheming Ruan Robert J. Cherney T.G. Murali Dhar James Neels Carolyn A. Weigelt John S. Sack Anurag S. Srivastava Lyndon A.M. Cornelius Joseph A. Tino Kevin Stefanski Xiaomei Gu Jenny Xie Vojkan Susulic Xiaoxia Yang Melissa Yarde-Chinn Stacey Skala Ruth Bosnius Michael A. Poss 《Bioorganic & medicinal chemistry letters》2017,27(4):855-861
As demonstrated in preclinical animal models, the disruption of PI3Kδ expression or its activity leads to a decrease in inflammatory and immune responses. Therefore, inhibition of PI3Kδ may provide an alternative treatment for autoimmune diseases, such as RA, SLE, and respiratory ailments. Herein, we disclose the identification of 7-(3-(piperazin-1-yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine derivatives as highly potent, selective and orally bioavailable PI3Kδ inhibitors. The lead compound demonstrated efficacy in an in vivo mouse KLH model. 相似文献