共查询到20条相似文献,搜索用时 15 毫秒
1.
Sobhana Babu Boga Abdul-Basit Alhassan Jian Liu Deodial Guiadeen Arto Krikorian Xiaolei Gao James Wang Younong Yu Rajan Anand Shilan Liu Chundao Yang Hao Wu Jiaqiang Cai Hugh Zhu Jagdish Desai Kevin Maloney Ying-Duo Gao Thierry O. Fischmann Joseph A. Kozlowski 《Bioorganic & medicinal chemistry letters》2017,27(16):3939-3943
8-Amino-imidazo[1,5-a]pyrazine-based Bruton’s tyrosine kinase (BTK) inhibitors, such as 6, exhibited potent inhibition of BTK but required improvements in both kinase and hERG selectivity (Liu et al., 2016; Gao et al., 2017). In an effort to maintain the inhibitory activity of these analogs and improve their selectivity profiles, we carried out SAR exploration of groups at the 3-position of pyrazine compound 6. This effort led to the discovery of the morpholine group as an optimized pharmacophore. Compounds 13, 23 and 38 displayed excellent BTK potencies, kinase and hERG selectivities, and pharmacokinetic profiles. 相似文献
2.
Xiaojing Wang Steven Magnuson Rich Pastor Eric Fan Huiyong Hu Vickie Tsui Wei Deng Jeremy Murray Micah Steffek Heidi Wallweber John Moffat Jason Drummond Grace Chan Eric Harstad Allen J. Ebens 《Bioorganic & medicinal chemistry letters》2013,23(11):3149-3153
Pim kinases are promising targets for the development of cancer therapeutics. Among the three Pim isoforms, Pim-2 is particularly important in multiple myeloma, yet is the most difficult to inhibit due to its high affinity for ATP. We identified compound 1 via high throughput screening. Using property-based drug design and co-crystal structures with Pim-1 kinase to guide analog design, we were able to improve potency against all three Pim isoforms including a significant 10,000-fold gain against Pim-2. Compound 17 is a novel lead with low picomolar potency on all three Pim kinase isoforms. 相似文献
3.
Micheli F Cavanni P Di Fabio R Marchioro C Donati D Faedo S Maffeis M Sabbatini FM Tranquillini ME 《Bioorganic & medicinal chemistry letters》2006,16(5):1342-1345
Exploiting the SAR of the known pyrrole derivatives, a new class of mGluR1 antagonists was developed through a cyclization of the C-2 position on the pyrrole N-1 nitrogen. The resulting pyrrolo[1,2-a]pyrazinones are potent and noncompetitive antagonists. 相似文献
4.
Bei Li Oana M. Cociorva Tyzoon Nomanbhoy Helge Weissig Qiang Li Kai Nakamura Marek Liyanage Melissa C. Zhang Ann Y. Shih Arwin Aban Yi Hu Julia Cajica Lan Pham John W. Kozarich Kevin R. Shreder 《Bioorganic & medicinal chemistry letters》2013,23(18):5217-5222
As the result of a rhJNK1 HTS, the imidazo[1,2-a]quinoxaline 1 was identified as a 1.6 μM rhJNK1 inhibitor. Optimization of this compound lead to AX13587 (rhJNK1 IC50 = 160 nM) which was co-crystallized with JNK1 to identify key molecular interactions. Kinase profiling against 125+ kinases revealed AX13587 was an inhibitor of JNK, MAST3, and MAST4 whereas its methylene homolog AX14373 (native JNK1 IC50 = 47 nM) was a highly specific JNK inhibitor. 相似文献
5.
Zhaoyang Meng Jeffrey P. Ciavarri Andrew McRiner Yinyan Zhao Lianyun Zhao Panduranga Adulla Reddy Xingmin Zhang Thierry O. Fischmann Charles Whitehurst M. Arshad Siddiqui 《Bioorganic & medicinal chemistry letters》2013,23(10):2863-2867
Chemistry has been developed to access both imidazo[1,2-a]pyrazines and imidazo[1,2-c]pyrimidines. Small structural modifications in both series led to a switch of potency between two kinases involved in mediating cell cycle checkpoint control, CHK1 and MK2. 相似文献
6.
Lakshmaiah Gingipalli Michael H. Block Larry Bao Emma Cooke Les A. Dakin Christopher R. Denz Andrew D. Ferguson Jeffrey W. Johannes Nicholas A. Larsen Paul D. Lyne Timothy W. Pontz Tao Wang Xiaoyun Wu Allan Wu Hai-Jun Zhang Xiaolan Zheng James E. Dowling Michelle L. Lamb 《Bioorganic & medicinal chemistry letters》2018,28(8):1336-1341
The design and synthesis of a novel series of 2,6-disubstituted pyrazine derivatives as CK2 kinase inhibitors is described. Structure-guided optimization of a 5-substituted-3-thiophene carboxylic acid screening hit (3a) led to the development of a lead compound (12b), which shows inhibition in both enzymatic and cellular assays. Subsequent design and hybridization efforts also led to the unexpected identification of analogs with potent PIM kinase activity (14f). 相似文献
7.
《Bioorganic & medicinal chemistry letters》2014,24(19):4650-4653
We report the design, synthesis, and biological evaluation of imidazopyridine-based peptidomimetics based on the substrate consensus sequence of Akt, an AGC family serine/threonine kinase hyperactivated in over 50% of human tumors. Our ligand-based approach led to the identification of novel substrate mimetic inhibitors of Akt1 featuring an unnatural extended dipeptide surrogate. Compound 11 inhibits Akt isoforms in the sub-micromolar range and exhibits improved proteolytic stability relative to a parent pentapeptide. 相似文献
8.
György Szabó Róbert Kiss Dóra Páyer-Lengyel Krisztina Vukics Judit Szikra Andrea Baki László Molnár János Fischer György M. Keserű 《Bioorganic & medicinal chemistry letters》2009,19(13):3471-3475
Hit-to-lead optimization of a novel series of N-alkyl-N-[2-oxo-2-(4-aryl-4H-pyrrolo[1,2-a]quinoxaline-5-yl)-ethyl]-carboxylic acid amides, derived from a high throughput screening (HTS) hit, are described. Subsequent optimization led to identification of in vitro potent cannabinoid 1 receptor (CB1R) antagonists representing a new class of compounds in this area. 相似文献
9.
《Journal of enzyme inhibition and medicinal chemistry》2013,28(2):204-215
Attenuation of protein kinases by selective inhibitors is an extremely active field of activity in anticancer drug development. Therefore, Akt, a serine/threonine protein kinase, also known as protein kinase B (PKB), represents an attractive potential target for therapeutic intervention. Recent efforts in the development and biological evaluation of small molecule inhibitors of Akt have led to the identification of novel inhibitors with various heterocycle scaffolds. Based on previous results obtained on the antiproliferative activities of new pyrrolo[1,2-a]quinoxalines, a novel series was designed and synthesized from various substituted phenyl-1H-pyrrole-2-carboxylic acid alkyl esters via a multistep heterocyclization process. These new compounds were tested for their in vitro ability to inhibit the proliferation of the human leukemic cell lines K562, U937, and HL60, and the breast cancer cell line MCF7. The first biological evaluation of our new substituted pyrrolo[1,2-a]quinoxalines showed antiproliferative activity against the tested cell lines. From a general SAR point of view, these preliminary biological results highlight the importance of substitution at the C-4 position of the pyrroloquinoxaline scaffold by a benzylpiperidinyl fluorobenzimidazole group, and also the need for a functionalization on the pyrrole ring. 相似文献
10.
Nishiguchi GA Atallah G Bellamacina C Burger MT Ding Y Feucht PH Garcia PD Han W Klivansky L Lindvall M 《Bioorganic & medicinal chemistry letters》2011,21(21):6366-6369
A series of novel 3,5-disubstituted indole derivatives as potent and selective inhibitors of all three members of the Pim kinase family is described. High throughput screen identified a pan-Pim kinase inhibitor with a promiscuous scaffold. Guided by structure-based drug design, SAR of the series afforded a highly selective indole chemotype that was further developed into a potent set of compounds against Pim-1, 2, and 3 (Pim-1 and Pim-3: IC(50)≤2nM and Pim-2: IC(50)≤100nM). 相似文献
11.
Zeng H Belanger DB Curran PJ Shipps GW Miao H Bracken JB Arshad Siddiqui M Malkowski M Wang Y 《Bioorganic & medicinal chemistry letters》2011,21(19):5870-5875
A series of substituted imidazo[1,2-a]pyrazin-8-amines were discovered as novel breast tumor kinase (Brk)/protein tyrosine kinase 6 (PTK6) inhibitors. Tool compounds with low-nanomolar Brk inhibition activity, high selectivity towards other kinases and desirable DMPK properties were achieved to enable the exploration of Brk as an oncology target. 相似文献
12.
Hamdouchi C Zhong B Mendoza J Collins E Jaramillo C De Diego JE Robertson D Spencer CD Anderson BD Watkins SA Zhang F Brooks HB 《Bioorganic & medicinal chemistry letters》2005,15(7):1943-1947
Structure-based design approach was successfully used to guide the evolution of imidazopyridine scaffold yielding new structural class of highly selective inhibitors of cyclin dependent kinases that were able to form a new interaction with an identified residue of the protein, Lys89. Compounds from this series have shown no detectable effect when tested against a representative set of other serine/threonine kinases such as GSK3beta, CAMKII, PKA, PKC-alpha,beta,epsilon,gamma. Compound 2i inhibits proliferation in HCT 116 cells in tissue culture. Synthesis, co-crystal structure of CDK2 in complex with compound 2i, and preliminary SAR study are disclosed. 相似文献
13.
《Bioorganic & medicinal chemistry》2014,22(4):1303-1312
Chromosomal translocations involving anaplastic lymphoma kinase (ALK) are the driving mutations for a range of cancers and ALK is thus considered an attractive therapeutic target. We synthesized a series of functionalized benzo[4,5]imidazo[1,2-c]pyrimidines and benzo[4,5]imidazo[1,2-a]pyrazines by an aza-Graebe–Ullman reaction, followed by palladium-catalyzed cross-coupling reactions. A sequential regioselective cross-coupling route is reported for the synthesis of unsymmetrically disubstituted benzo[4,5]imidazo[1,2-a]pyrazines. The inhibition of ALK was evaluated and compound 19 in particular showed good activity against both the wild type and crizotinib-resistant L1196M mutant in vitro and in ALK-transfected BaF3 cells. 相似文献
14.
Maria P. Giovannoni Nicoletta Cesari Alessia Graziano Claudia Vergelli Claudio Biancalani Pierfrancesco Biagini 《Journal of enzyme inhibition and medicinal chemistry》2013,28(3):309-318
A series of pyrrolo[2,3-d]pyridazinones was synthesized and tested for their inhibitory activity on PDE4 subtypes A, B and D and selectivity toward Rolipram high affinity binding site (HARBS). New agents with interesting profile were reported; in particular compound 9e showed a good PDE4 subtype selectivity, being 8 times more potent (IC50 = 0.32 μM) for PDE4B (anti-inflammatory) than for PDE4D (IC50 = 2.5 μM), generally considered the subtype responsible for emesis. Moreover the ratio HARBS/PDE4B was particularly favourable for 9e (147), suggesting that the best arranged groups around the pyrrolopyridazinone core are an isopropyl at position-1, an ethoxycarbonyl at position-2, together with an ethyl group at position-6.For compounds 8 and 15a the ability to inhibit TNFα production in PBMC was evaluated and the results are consistent with their PDE4 inhibitory activity. 相似文献
15.
Giorgio Cozza Stefania Sarno Maria Ruzzene Cristina Girardi Andrzej Orzeszko Zygmunt Kazimierczuk Giuseppe Zagotto Emanuela Bonaiuto Maria Luisa Di Paolo Lorenzo A. Pinna 《Biochimica et Biophysica Acta - Proteins and Proteomics》2013,1834(7):1402-1409
Advantage has been taken of the relative promiscuity of commonly used inhibitors of protein kinase CK2 to develop compounds that can be exploited for the selective inhibition of druggable kinases other than CK2 itself. Here we summarize data obtained by altering the scaffold of CK2 inhibitors to give rise to novel selective inhibitors of DYRK1A and to a powerful cell permeable dual inhibitor of PIM1 and CK2. In the former case one of the new compounds, C624 (naphto [1,2-b]benzofuran-5,9-diol) displays a potency comparable to that of the first-in-class DYRK1A inhibitor, harmine, lacking however the drawback of drastically inhibiting monoamine oxidase-A (MAO-A) as harmine does. On the other hand the promiscuous CK2 inhibitor 4,5,6,7-tetrabromo-1H-benzimidazole (TBI,TBBz) has been derivatized with a sugar moiety to generate a 1-(β-D-2′-deoxyribofuranosyl)-4,5,6,7-tetrabromo-1H-benzimidazole (TDB) compound which inhibits PIM1 and CK2 with comparably high efficacy (IC50 values < 100 nM) and remarkable selectivity. TDB, unlike other dual PIM1/CK2 inhibitors described in the literature is readily cell permeable and displays a cytotoxic effect on cancer cells consistent with concomitant inhibition of both its onco-kinase targets. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases (2012). 相似文献
16.
Claridge S Raeppel F Granger MC Bernstein N Saavedra O Zhan L Llewellyn D Wahhab A Deziel R Rahil J Beaulieu N Nguyen H Dupont I Barsalou A Beaulieu C Chute I Gravel S Robert MF Lefebvre S Dubay M Pascal R Gillespie J Jin Z Wang J Besterman JM MacLeod AR Vaisburg A 《Bioorganic & medicinal chemistry letters》2008,18(9):2793-2798
A series of thieno[3,2-b]pyridine-based inhibitors of c-Met and VEGFR2 tyrosine kinases is described. The compounds demonstrated potency with IC50 values in the low nanomolar range in vitro while the lead compound also showed in vivo activity against various human tumor xenograft models in mice. Further exploration of this class of compounds is underway. 相似文献
17.
《Journal of enzyme inhibition and medicinal chemistry》2013,28(5):657-667
A novel series of isoindolo[2,1-a]quinoxaline and indolo[1,2-a]quinoxaline derivatives was synthesized and evaluated in vitro against various human cancer cell lines for antiproliferative activity. These new compounds displayed activity against leukemia and breast cancer cell lines in the 3- to 18-µM concentration range. 相似文献
18.
Pál Gyulavári Bálint Szokol István Szabadkai Diána Brauswetter Péter Bánhegyi Attila Varga Péter Markó Sándor Boros Eszter Illyés Csaba Szántai-Kis Marcell Krekó Zsófia Czudor László Őrfi 《Bioorganic & medicinal chemistry letters》2018,28(19):3265-3270
Aurora kinases as regulators of cell division have become promising therapeutic targets recently. Here we report novel, low molecular weight benzothiophene-3-carboxamide derivatives designed and optimized for inhibiting Aurora kinases. The most effective compound 36 inhibits Aurora kinases in vitro in the nanomolar range and diminishes HCT 116 cell viability blocking cytokinesis and inducing apoptosis. According to western blot analysis, the lead molecule inhibits Aurora kinases equipotently to VX-680 (Tozasertib) and similarly synergizes with other targeted drugs. 相似文献
19.
Fink BE Norris D Mastalerz H Chen P Goyal B Zhao Y Kim SH Vite GD Lee FY Zhang H Oppenheimer S Tokarski JS Wong TW Gavai AV 《Bioorganic & medicinal chemistry letters》2011,21(2):781-785
A novel series of 5-((4-aminopiperidin-1-yl)methyl)-pyrrolo[2,1-f][1,2,4]triazin-4-amines with small aniline substituents at the C4 position were optimized for dual EGFR and HER2 protein tyrosine kinase inhibition. Compound 8l exhibited promising oral efficacy in both EGFR and HER2-driven human tumor xenograft models. 相似文献
20.
Xiao Ding Luigi Piero Stasi Ming-Hsun Ho Baowei Zhao Hailong Wang Kai Long Qiongfeng Xu Yingxia Sang Changhui Sun Huan Hu Haihua Yu Zehong Wan Lizhen Wang Colin Edge Qian Liu Yi Li Kelly Dong Xiaoming Guan Feng Ren 《Bioorganic & medicinal chemistry letters》2018,28(9):1615-1620
Inhibition of LRRK2 kinase activity with small molecules has emerged as a potential novel therapeutic treatment for Parkinson’s disease. Herein we disclose the discovery of a 4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-2-amine series as potent LRRK2 inhibitors identified through a kinase-focused set screening. Optimization of the physicochemical properties and kinase selectivity led to the discovery of compound 7, which exhibited potent in vitro inhibition of LRRK2 kinase activity, good physicochemical properties and kinase selectivity across the kinome. Moreover, compound 7 was able to penetrate into the CNS, and in vivo pharmacology studies revealed significant inhibition of Ser935 phosphorylation in the brain of both rats (30 and 100?mg/kg) and mice (45?mg/kg) following oral administration. 相似文献