共查询到20条相似文献,搜索用时 671 毫秒
1.
《Bioorganic & medicinal chemistry letters》2014,24(14):3142-3145
The design, synthesis, and capacity to inhibit HIF prolyl 4-hydroxylases (PHDs) are described for 2-[2-(3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetamide analogs. These analogs revealed two kinds of novel scaffolds as PHD2 inhibitors. Synthetic routes were developed for the preparation of their analogs containing the new scaffolds. In addition, the structure–activity relationship (SAR) of the 2-[2-(3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetamide derivatives and their biological activities were reported. The complex structure of compound 18 with PHD2 was also obtained for the purpose of more efficient lead optimization. 相似文献
2.
Sleebs BE Nikolakopoulos G Street IP Falk H Baell JB 《Bioorganic & medicinal chemistry letters》2011,21(19):5992-5994
4-Aminobenzothieno[3,2-d]pyrimidines were previously identified in a high throughput screening campaign as LIMK1 inhibitors. Scaffold reversal led to the identification of a series of simple 5,6-substituted 4-aminothieno[2,3-d]pyrimidines with low micromolar inhibition of LIMK1. 相似文献
3.
Andrew F. Donnell Paul J. Dollings John A. Butera Arlene J. Dietrich Kerri K. Lipinski Afshin Ghavami Warren D. Hirst 《Bioorganic & medicinal chemistry letters》2010,20(7):2163-2167
Substituted pyridazino[4,5-b]indolizines were identified as potent and selective PDE4B inhibitors. We describe the structure–activity relationships generated around an HTS hit that led to a series of compounds with low nanomolar affinity for PDE4B and high selectivity over the PDE4D subtype. 相似文献
4.
Zhang N Wu B Wissner A Powell DW Rabindran SK Kohler C Boschelli F 《Bioorganic & medicinal chemistry letters》2002,12(3):423-425
A series of 4-anilino-3-cyanobenzo[g]quinolines was prepared as potent kinase inhibitors. Compared with their bicyclic 4-anilino-3-cyanoquinoline analogues, the tricyclic 4-anilino-3-cyanobenzo[g]quinolines are less active against EGF-R kinase, equally active against MAPK kinase (MEK), and more active against Src kinase. For Src kinase inhibition, the best activity is obtained when both the 7- and 8-positions are substituted with alkoxy groups. Several of these kinase inhibitors show potent growth inhibitory activity in tumor cells. 相似文献
5.
Sanchez-Martinez C Shih C Faul MM Zhu G Paal M Somoza C Li T Kumrich CA Winneroski LL Xun Z Brooks HB Patel BK Schultz RM DeHahn TB Spencer CD Watkins SA Considine E Dempsey JA Ogg CA Campbell RM Anderson BA Wagner J 《Bioorganic & medicinal chemistry letters》2003,13(21):3835-3839
The synthesis of new analogues of Arcyriaflavin A in which one indole ring is replaced by an aryl or heteroaryl ring is described. These new series of aryl[a]pyrrolo[3,4-c]carbazoles were evaluated as inhibitors of Cyclin D1-CDK4. A potent and selective D1-CDK4 inhibitor, 7a (D1-CDK4 IC(50)=45 nM), has been identified. The potency, selectivity profile against other kinases, and structure-activity relationship (SAR) trends of this class of compounds are discussed. 相似文献
6.
Makoto Hamada Tetsuo Takayama Tsuyoshi Shibata Akira Hiratate Masato Takahashi Miyoko Yashiro Noriko Takayama Lisa Okumura-Kitajima Hiroko Koretsune Hiromitsu Kajiyama Takumi Naruse Sota Kato Hiroki Takano Hiroyuki Kakinuma 《Bioorganic & medicinal chemistry letters》2018,28(10):1725-1730
Prolyl hydroxylase domain-containing protein (PHD) inhibitors are useful as orally administered agents for the treatment of renal anemia. Based on the common structures of known PHD inhibitors, we found novel PHD inhibitor 1 with a 2-[(4-hydroxy-6-oxo-2,3-dihydro-1H-pyridine-5-carbonyl)amino]acetic acid motif. The PHD2-inhibitory activity, lipophilicity (CLogP), and PK profiles (hepatocyte metabolism, protein binding, and/or elimination half-life) of this inhibitor were used as the evaluation index to optimize the structure and eventually discovered clinical candidate 42 as the suitable compound. Compound 42 was demonstrated to promote the production of erythropoietin (EPO) following oral administration in mice and rats. The predicted half-life of this compound in humans was 1.3–5.6?h, therefore, this drug may be expected to administer once daily with few adverse effects caused by excessive EPO production. 相似文献
7.
Guanghui Deng Baowei Zhao Yingli Ma Qiongfeng Xu Hailong Wang Liuqing Yang Qing Zhang Taylor B. Guo Wei Zhang Yang Jiao Xin Cai Jinqiang Zhang Houfu Liu Xiaoming Guan Hongtao Lu Jianing Xiang John D. Elliott Xichen Lin Feng Ren 《Bioorganic & medicinal chemistry》2013,21(21):6349-6358
We have discovered a novel complex crystal structure of the PHD2 enzyme with its inhibitor, the 2,8-diazaspiro[4.5]decan-1-one analogue 4b. The widely reported salt bridge between Arg383 of the enzyme and its inhibitors in all complex structures published thus far was not observed in our case. In our complex structure compound 4b forms several novel interactions with the enzyme, which include a hydrogen bond with Arg322, a π-cation interaction with Arg322, a π–π stacking with Trp389, and a π–π stacking with His313. Guided by the structural information, SAR studies were performed on the 2,8-diazaspiro[4.5]decan-1-one series leading to the discovery of compound 9p with high potency and good oral pharmacokinetic profile in mice. 相似文献
8.
Wissner A Hamann PR Nilakantan R Greenberger LM Ye F Rapuano TA Loganzo F 《Bioorganic & medicinal chemistry letters》2004,14(6):1411-1416
The syntheses and EGFR kinase inhibitory activity of a series of 6-substituted-4-anilino [1,7] and [1,8] naphthyridine-3-carbonitriles are described. Both reversible and irreversible binding inhibitors were prepared. These series were compared with each other and with the corresponding 4-anilinoquinoline-3-carbonitriles. Compounds having a 1,7-naphthyridine core structure can retain high potency while those with a 1,8-naphthyridine core are significantly less active. These results are consistent with molecular modeling observations. 相似文献
9.
José-Ignacio Andrés Peter Buijnsters Meri De Angelis Xavier Langlois Frederik Rombouts Andrés A. Trabanco Greet Vanhoof 《Bioorganic & medicinal chemistry letters》2013,23(3):785-790
The synthesis, preliminary evaluation and structure–activity relationship (SAR) of a series of 1-aryl-4-methyl[1,2,4]triazolo[4,3-a]quinoxalines as dual phosphodiesterase 2/phosphodiesterase 10 (PDE2/PDE10) inhibitors are described. From this investigation compound 31 was identified, showing good combined potency, acceptable brain uptake and high selectivity for both PDE2 and PDE10 enzymes. Compound 31 was subjected to a microdosing experiment in rats, showing preferential distribution in brain areas where both PDE2 and PDE10 are highly expressed. These promising results may drive the further development of highly potent combined PDE2/PDE10 inhibitors, or even of selective inhibitors of PDE2 and/or PDE10. 相似文献
10.
《Bioorganic & medicinal chemistry letters》2019,29(18):2595-2603
Inhibitors of the Hippo signaling pathway have been demonstrated to have a potential clinical application in cases such as tissue repair and organ regeneration. However, there is a lack of potent Hippo pathway inhibitors at present. Herein we report the discovery of a series of 1,8-disubstituted-[1,2,3]triazolo[4,5-c]quinoline derivatives as a new class of Hippo pathway inhibitors by utilizing a cell line-based screening model (A549-CTGF). Structure-activity relationship (SAR) of these compounds was also discussed. The most potent compound in the A549-CTGF cell assay, 11g, was then evaluated by real-time PCR and immunofluorescence assays. Overall, this study provides a starting point for later drug discovery targeting the Hippo signaling pathway. 相似文献
11.
Chuangxing Guo Angelica Linton Mehran Jalaie Susan Kephart Martha Ornelas Mason Pairish Samantha Greasley Paul Richardson Karen Maegley Michael Hickey John Li Xin Wu Xiaodong Ji Zhi Xie 《Bioorganic & medicinal chemistry letters》2013,23(11):3358-3363
The M2 isoform of pyruvate kinase is an emerging target for antitumor therapy. In this letter, we describe the discovery of 2-((1H-benzo[d]imidazol-1-yl)methyl)-4H-pyrido[1,2-a]pyrimidin-4-ones as potent and selective PKM2 activators which were found to have a novel binding mode. The original lead identified from high throughput screening was optimized into an efficient series via computer-aided structure-based drug design. Both a representative compound from this series and an activator described in the literature were used as molecular tools to probe the biological effects of PKM2 activation on cancer cells. Our results suggested that PKM2 activation alone is not sufficient to alter cancer cell metabolism. 相似文献
12.
Jian-kang Jiang Xiuli Huang Khalida Shamim Paresma R. Patel Arthur Lee Amy Q. Wang Kimloan Nguyen Gregory Tawa Gregory D. Cuny Paul B. Yu Wei Zheng Xin Xu Philip Sanderson Wenwei Huang 《Bioorganic & medicinal chemistry letters》2018,28(20):3356-3362
The pyrazolo[1,5-a]pyrimidine LDN-193189 is a potent inhibitor of activin receptor-like kinase 2 (ALK2) but is nonselective for highly homologous ALK3 and shows only modest kinome selectivity. Herein, we describe the discovery of a novel series of potent and selective ALK2 inhibitors by replacing the quinolinyl with a 4-(sulfamoyl)naphthyl, yielding ALK2 inhibitors that exhibit not only excellent discrimination versus ALK3 but also high kinome selectivity. In addition, the optimized compound 23 demonstrates good ADME and in vivo pharmacokinetic properties. 相似文献
13.
Dwyer MP Paruch K Labroli M Alvarez C Keertikar KM Poker C Rossman R Fischmann TO Duca JS Madison V Parry D Davis N Seghezzi W Wiswell D Guzi TJ 《Bioorganic & medicinal chemistry letters》2011,21(1):467-470
The synthesis and hit-to-lead SAR development of a pyrazolo[1,5-a]pyrimidine hit 4 is described leading to a series of potent, selective CHK1 inhibitors such as compound 17r. In the Letter, the further utility of the pyrazolo[1,5-a]pyrimidine template for the development of potent, selective kinase inhibitors is detailed. 相似文献
14.
《Bioorganic & medicinal chemistry letters》2014,24(18):4538-4541
Inhibition of the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway by PI3K/mTOR dual inhibitors provides a promising new approach to the treatment of cancers. In this Letter, we identified structurally novel and potent PI3K/mTOR dual inhibitors from a series of 2-amino-4-methylpyrido[2,3-d]pyrimidine derivatives. Their synthesis and structure–activity relationships are reported. 相似文献
15.
Hyo-Nim Shin Seon Hee Seo Hyunah Choo Gyochang Kuem Kyung Il Choi Ghilsoo Nam 《Bioorganic & medicinal chemistry letters》2013,23(5):1193-1196
A novel series of 5(R)-[1,2,3]triazolylmethyl and (5R)-[(4-F-[1,2,3]triazolyl)methyl]oxazolidinones having various piperidine group were synthesized and evaluated antibacterial activity against clinically isolated resistant strains of Gram-positive and Gram-negative bacteria. The compound 12a having exo-cyanoethylidene group in the 4-position of piperidine ring was found to be two to threefold more potent than the linezolid against penicillin-resistant Staphylococcus pneumonia and Staphylococcus agalactiae, and also exhibited reduced MAO-B inhibitory activity. 相似文献
16.
A Afonso J Kelly J Weinstein L James W R Bishop 《Bioorganic & medicinal chemistry letters》1999,9(13):1875-1880
A series of 3-substituted analogs 3 of 4-(3-bromo-8-methyl-10-methoxy-6,11-dihydro-5H-benzo[5,6]-cyclohepta[1,2 b]pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N-oxide 2 was prepared and evaluated as FPT inhibitors. The objective of this study was to identify other substituents at C3 in this series of FPT inhibitors that would have the FPT potency enhancement similar to that found for a C3 bromo substituent. The 3-methyl analog 17b was found to be tenfold less active than 2, and other C3 substituents having more steric bulk were found to cause a further reduction in activity. 相似文献
17.
Kevin R. Shreder Julia Cajica Lingling Du Allister Fraser Yi Hu Yasushi Kohno Emme C.K. Lin Steve J. Liu Eric Okerberg Lan Pham Jiangyue Wu John W. Kozarich 《Bioorganic & medicinal chemistry letters》2009,19(16):4743-4746
The hit-to-lead optimization of the HNE inhibitor 5-methyl-2-(2-phenoxy-pyridin-3-yl)-benzo[d][1,3]oxazin-4-one is described. A structure–activity relationship study that focused on the 5 and 7 benzoxazinone positions yielded the optimized 5-ethyl-7-methoxy-benzo[d][1,3]oxazin-4-one core structure. 2-[2-(4-Methyl-piperazin-1-yl)-pyridin-3-yl] derivatives of this core were shown to yield HNE inhibitors of similar potency with significantly different stabilities in rat plasma. 相似文献
18.
Eckhardt M Hauel N Himmelsbach F Langkopf E Nar H Mark M Tadayyon M Thomas L Guth B Lotz R 《Bioorganic & medicinal chemistry letters》2008,18(11):3158-3162
Systematic variations of the xanthine scaffold in close analogs of development compound BI 1356 led to the class of 3,5-dihydro-imidazo[4,5-d]pyridazin-4-ones which provided, after substituent screening, a series of highly potent DPP-4 inhibitors. 相似文献
19.
Buckmelter AJ Ren L Laird ER Rast B Miknis G Wenglowsky S Schlachter S Welch M Tarlton E Grina J Lyssikatos J Brandhuber BJ Morales T Randolph N Vigers G Martinson M Callejo M 《Bioorganic & medicinal chemistry letters》2011,21(4):1248-1252
Virtual and high-throughput screening identified imidazo[1,2-a]pyrazines as inhibitors of B-Raf. We describe the rationale, SAR, and evolution of the initial hits to a series of furo[2,3-c]pyridine indanone oximes as highly potent and selective inhibitors of B-Raf. 相似文献
20.
Imran Ali Jooyun Lee Areum Go Gildon Choi Kwangho Lee 《Bioorganic & medicinal chemistry letters》2017,27(20):4606-4613
Bromodomain and extra-terminal (BET) proteins, a class of epigenetic reader domains has emerged as a promising new target class for small molecule drug discovery for the treatment of cancer, inflammatory, and autoimmune diseases. Starting from in silico screening campaign, herein we report the discovery of novel BET inhibitors based on [1,2,4]triazolo[4,3-a]quinoxaline scaffold and their biological evaluation. The hit compound was optimized using the medicinal chemistry approach to the lead compound with excellent inhibitory activities against BRD4 in the binding assay. The substantial antiproliferative activities in human cancer cell lines, promising drug-like properties, and the selectivity for the BET family make the lead compound (13) as a novel BRD4 inhibitor motif for anti-cancer drug discovery. 相似文献