共查询到20条相似文献,搜索用时 15 毫秒
1.
Rie Nishikawa-Shimono Yoshinori Sekiguchi Takeshi Koami Madoka Kawamura Daisuke Wakasugi Kazuhito Watanabe Shunichi Wakahara Kayo Kimura Susumu Yamanobe Tetsuo Takayama 《Bioorganic & medicinal chemistry》2013,21(24):7674-7685
In this study, we describe the synthesis and structure–activity relationship (SAR) of a series of isoquinoline chemoattractant receptor–homologous molecule expressed on Th2 cells (CRTH2) antagonists. TASP0376377 (15-20), one of the most potent compounds, showed a potent binding affinity (IC50 = 19 nM) in addition to the excellent functional antagonist activity (IC50 = 13 nM). Moreover, the efficacy of this compound in a chemotaxis assay (IC50 = 23 nM) was in good agreement with its potency as a CRTH2 antagonist. In addition, 15-20 exhibited greater selectivity in binding to CRTH2 than to the DP1 prostanoid receptor (IC50 >1 μM) or the enzymes COX-1 and COX-2 (IC50 >10 μM). 相似文献
2.
Frank Ruebsam Chinh V. Tran Lian-Sheng Li Sun Hee Kim Alan X. Xiang Yuefen Zhou Julie K. Blazel Zhongxiang Sun Peter S. Dragovich Jingjing Zhao Helen M. McGuire Douglas E. Murphy Martin T. Tran Nebojsa Stankovic David A. Ellis Alberto Gobbi Richard E. Showalter Stephen E. Webber Amit M. Shah Mei Tsan Leo Kirkovsky 《Bioorganic & medicinal chemistry letters》2009,19(2):451-458
5,6-Dihydro-1H-pyridin-2-one analogs were discovered as a novel class of inhibitors of genotype 1 HCV NS5B polymerase. Among these, compound 4ad displayed potent inhibitory activities in biochemical and replicon assays (IC50 (1b) < 10 nM; IC50 (1a) < 25 nM, EC50 (1b) = 16 nM), good in vitro DMPK properties, as well as moderate oral bioavailability in monkeys (F = 24%). 相似文献
3.
Laszlo Revesz Achim Schlapbach Reiner Aichholz Janet Dawson Roland Feifel Stuart Hawtin Amanda Littlewood-Evans Guido Koch Markus Kroemer Henrik Möbitz Clemens Scheufler Juraj Velcicky Christine Huppertz 《Bioorganic & medicinal chemistry letters》2010,20(15):4719-4723
Spirocyclopropane- and spiroazetidine-substituted tetracycles 13D–E and 16A are described as orally active MK2 inhibitors. The spiroazetidine derivatives are potent MK2 inhibitors with IC50 <3 nM and inhibit the release of TNFα (IC50<0.3 μM) from hPBMCs and hsp27 phosphorylation in anisomycin stimulated THP-1 cells. The spirocyclopropane analogues are less potent against MK2 (IC50 = 0.05–0.23 μM), less potent in cells (IC50 <1.1 μM), but show good oral absorption. Compound 13E (100 mg/kg po; bid) showed oral activity in rAIA and mCIA, with significant reduction of swelling and histological score. 相似文献
4.
Pyrrole derivatives as potent inhibitors of lymphocyte-specific kinase: Structure,synthesis, and SAR
Tetsuo Takayama Hiroki Umemiya Hideaki Amada Tetsuya Yabuuchi Fumiyasu Shiozawa Hironori Katakai Akiko Takaoka Akie Yamaguchi Mayumi Endo Masakazu Sato 《Bioorganic & medicinal chemistry letters》2010,20(1):108-111
We have described the synthesis, enzyme inhibitory activity, structure–activity relationships, and proposed binding mode of a novel series of pyrrole derivatives as lymphocyte-specific kinase (Lck) inhibitors. The most potent analogs exhibited good enzyme inhibitory activity (IC50s <10 nM) for Lck kinase inhibition. 相似文献
5.
《Bioorganic & medicinal chemistry letters》2014,24(24):5683-5687
A series of 3,6-disubstituted dihydropyrones were identified as inhibitors of human lactate dehydrogenase (LDH)-A. Structure activity relationships were explored and a series of 6,6-spiro analogs led to improvements in LDHA potency (IC50 <350 nM). An X-ray crystal structure of an improved compound bound to human LDHA was obtained and it illustrated additional opportunities to enhance the potency of these compounds, resulting in the identification of 51 (IC50 = 30 nM). 相似文献
6.
Peter S. Dragovich Kenneth W. Bair Timm Baumeister Yen-Ching Ho Bianca M. Liederer Xiongcai Liu Yongbo Liu Thomas O’Brien Jason Oeh Deepak Sampath Nicholas Skelton Leslie Wang Weiru Wang Hongxing Wu Yang Xiao Po-wai Yuen Mark Zak Lei Zhang Xiaozhang Zheng 《Bioorganic & medicinal chemistry letters》2013,23(17):4875-4885
Potent nicotinamide phosphoribosyltransferase (NAMPT) inhibitors containing 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-derived ureas were identified using structure-based design techniques. The new compounds displayed improved aqueous solubilities, determined using a high-throughput solubility assessment, relative to previously disclosed urea and amide-containing NAMPT inhibitors. An optimized 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-derived compound exhibited potent anti-NAMPT activity (18; BC NAMPT IC50 = 11 nM; PC-3 antiproliferative IC50 = 36 nM), satisfactory mouse PK properties, and was efficacious in a PC-3 mouse xenograft model. The crystal structure of another optimized compound (29; NAMPT IC50 = 10 nM; A2780 antiproliferative IC50 = 7 nM) in complex with the NAMPT protein was also determined. 相似文献
7.
Wen-Ting Xu Ning Jin Jing Xu Yun-Gen Xu Qiu-Juan Wang Qi-Dong You 《Bioorganic & medicinal chemistry letters》2009,19(12):3283-3287
A novel series of substituted benzoylguanidine derivatives were designed and synthesized as potent NHE1 inhibitors. Most compounds can significantly inhibit NHE1-mediated platelet swelling in a concentration-dependent manner, among which compound 5f (IC50 = 3.60 nM) and 5l (IC50 = 4.48 nM) are 18 and 14 times respectively more potent than cariporide (IC50 = 65.0 nM). Furthermore, when tested in vivo and in vitro, compound 5f showed superior cardioprotective effects against SD rat myocardial ischemic-reperfusion injury over cariporide, representing a promising lead compound for further exploration. 相似文献
8.
Gary T. Wang Robert A. Mantei Robert D. Hubbard Julie L. Wilsbacher Qian Zhang Lora Tucker Xiaoming Hu Peter Kovar Eric F. Johnson Donald J. Osterling Jennifer Bouska Jieyi Wang Steven K. Davidsen Randy L. Bell George S. Sheppard 《Bioorganic & medicinal chemistry letters》2010,20(20):6067-6071
This Letter describes the lead discovery, optimization, and biological characterization of a series of substituted 4-amino-1H-pyrazolo[3,4-d]pyrimidines as potent inhibitors of IGF1R, EGFR, and ErbB2. The leading compound 11 showed an IGF1R IC50 of 12 nM, an EGFR (L858R) IC50 of 31 nM, and an ErbB2 IC50 of 11 nM, potent activity in cellular functional and anti-proliferation assays, as well as activity in an in vivo pharmacodynamic assay. 相似文献
9.
《Bioorganic & medicinal chemistry》2016,24(23):6206-6214
A series of novel non-covalent piperidine-containing dipeptidyl derivatives were designed, synthesized and evaluated as proteasome inhibitors. All target compounds were tested for their proteasome chymotrypsin-like inhibitory activities, and selected derivatives were evaluated for the anti-proliferation activities against two multiple myeloma (MM) cell lines RPMI 8226 and MM-1S. Among all of these compounds, eight exhibited significant proteasome inhibitory activities with IC50 less than 20 nM, and four are more potent than the positive control Carfilzomib. Compound 28 displayed the most potent proteasome inhibitory activity (IC50: 1.4 ± 0.1 nM) and cytotoxicities with IC50 values at 13.9 ± 1.8 nM and 9.5 ± 0.5 nM against RPMI 8226 and MM-1S, respectively. Additionally, the ex vivo blood cell proteasome inhibitory activities of compounds 24 and 27–29 demonstrated that the enzymatic metabolism in the whole blood could be well tolerated. All these experiments confirmed that the piperidine-containing non-covalent proteasome inhibitors are potential leads for exploring new anti-cancer drugs. 相似文献
10.
Teng-Kuang Yeh Ting-Yueh Tsai Tsu Hsu Jai-Hong Cheng Xin Chen Jen-Shin Song Horng-Shing Shy Mei-Chun Chiou Chia-Hui Chien Ya-Ju Tseng Chung-Yu Huang Kai-Chia Yeh Yu-Lin Huang Chih-Hsiang Huang Yu-Wen Huang Min-Hsien Wang Hung-Kuan Tang Yu-Sheng Chao Chiung-Tong Chen Weir-Torn Jiaang 《Bioorganic & medicinal chemistry letters》2010,20(12):3596-3600
A series of 2-[3-[2-[(2S)-2-cyano-1-pyrrolidinyl]-2-oxoethylamino]-3-methyl-1-oxobutyl]-based DPP-IV inhibitors with various monocyclic amines were synthesized. The structure–activity relationships (SAR) led to the discovery of potent DPP-IV inhibitors, having IC50 values of <100 nM with excellent selectivity over the closely related enzymes, DPP-II, DPP8, DPP9 and FAP (IC50 > 20 μM). Of these compounds, the analogues 12a, 12h and 12i exhibited a long-lasting ex vivo DPP-IV inhibition in rats. 相似文献
11.
Luc Demange Fatma Nait Abdellah Olivier Lozach Yoan Ferandin Nohad Gresh Laurent Meijer Hervé Galons 《Bioorganic & medicinal chemistry letters》2013,23(1):125-131
Cyclin dependent kinase 5 (CDK5) is a serine/threonine kinase belonging to the cyclin dependent kinase (CDK) family. CDK5 is involved in numerous neuronal diseases (including Alzheimer’s or Parkinson’s diseases, stroke, traumatic brain injury), pain signaling and cell migration. In the present Letter, we describe syntheses and biological evaluations of new 2,6,9-trisubstituted purines, structurally related to roscovitine, a promising CDK inhibitor currently in clinical trials (CDK1/Cyclin B, IC50 = 350 nM; CDK5/p25, IC50 = 200 nM). These new molecules were synthesized using an original Buchwald–Hartwig catalytic procedure; several compounds (3j, 3k, 3l, 3e, 4k, 6b, 6c) displayed potent kinase inhibitory potencies against CDK5 (IC50 values ranging from 17 to 50 nM) and showed significant cell death inducing activities (IC50 values ranging from 2 to 9 μM on SH-SY5Y). The docking of the inhibitors into the ATP binding domain of the CDK5 catalytic site highlighted the discriminatory effect of a hydrogen bond involving the CDK5 Lys-89. In addition, the calculated final energy balances for complexation measured for several inhibitors is consistent with the ranking of the IC50 values. Lastly, we observed that several compounds exhibit submicromolar activities against DYRK1A (dual specificity, tyrosine phosphorylation regulated kinase 1A), a kinase involved in Down syndrome and Alzheimer’s disease (3g, 3h, 4m; IC50 values ranging from 300 to 400 nM). 相似文献
12.
Mohamed S. Gomaa Andrew S.T. Lim S.C. Wilson Lau Ann-Marie Watts Nicola A. Illingworth Caroline E. Bridgens Gareth J. Veal Christopher P.F. Redfern Andrea Brancale Jane L. Armstrong Claire Simons 《Bioorganic & medicinal chemistry》2012,20(20):6080-6088
The role of all-trans-retinoic acid (ATRA) in the development and maintenance of many epithelial and neural tissues has raised great interest in the potential of ATRA and related compounds (retinoids) as pharmacological agents, particularly for the treatment of cancer, skin, neurodegenerative and autoimmune diseases. The use of ATRA or prodrugs as pharmacological agents is limited by a short half-life in vivo resulting from the activity of specific ATRA hydroxylases, CYP26 enzymes, induced by ATRA in liver and target tissues. For this reason retinoic acid metabolism blocking agents (RAMBAs) have been developed for treating cancer and a wide range of other diseases.The synthesis, CYP26A1 inhibitory activity and molecular modeling studies of novel methyl 3-[4-(arylamino)phenyl]-3-(azole)-2,2-dimethylpropanoates are presented. From this series of compounds clear SAR can be derived for 4-substitution of the phenyl ring with electron-donating groups more favourable for inhibitory activity. Both the methylenedioxyphenyl imidazole (17, IC50 = 8 nM) and triazole (18, IC50 = 6.7 nM) derivatives were potent inhibitors with additional binding interactions between the methylenedioxy moiety and the CYP26 active site likely to be the main factor. The 6-bromo-3-pyridine imidazole 15 (IC50 = 5.7 nM) was the most active from this series compared with the standards liarozole (IC50 = 540 nM) and R116010 (IC50 = 10 nM). 相似文献
13.
Taiji Goto Akiko Shiina Toshiharu Yoshino Kiyoshi Mizukami Kazuki Hirahara Osamu Suzuki Yoshitaka Sogawa Tomoko Takahashi Tsuyoshi Mikkaichi Naoki Nakao Mizuki Takahashi Masashi Hasegawa Shigeki Sasaki 《Bioorganic & medicinal chemistry letters》2013,23(11):3325-3328
2-Phenyl-4-piperidinyl-6,7-dihydrothieno[3,4-d]pyrimidine derivative (2) was found to be a new PDE4 inhibitor with moderate PDE4B activity (IC50 = 150 nM). A number of derivatives with a variety of 4-amino substituents and fused bicyclic pyrimidines were synthesized. Among these, 5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivative (18) showed potent PDE4B inhibitory activity (IC50 = 25 nM). Finally, N-propylacetamide derivative (31b) was determined as a potent inhibitor for both PDE4B (IC50 = 7.5 nM) and TNF-α production in mouse splenocytes (IC50 = 9.8 nM) and showed good in vivo anti-inflammatory activity in the LPS-induced lung inflammation model in mice (ID50 = 18 mg/kg). The binding mode of the new inhibitor (31e) in the catalytic site of PDE4B is presented based on an X-ray crystal structure of the ligand–enzyme complex. 相似文献
14.
Ludovica Morera Geoffray Labar Giorgio Ortar Didier M. Lambert 《Bioorganic & medicinal chemistry》2012,20(21):6260-6275
A series of (1H-benzo[d][1,2,3]triazol-1-yl)(4-benzylpiperazin-1-yl)methanones and of (1H-benzo[d][1,2,3]triazol-1-yl)(4-phenylpiperazin-1-yl)methanones has been prepared and tested on human fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). In the benzylpiperazinyl series, compound 29 (ML30) exhibited an IC50 value of 0.54 nM on MAGL, combined with a 1000-fold selectivity versus FAAH, while compounds 11 and 16 acted as potent dual FAAH-MAGL inhibitors (IC50 <10 nM). In the phenylpiperazinyl series, compounds 37, 38, 42, and 43 displayed IC50 values against MAGL in the nanomolar range, whilst being between one and two orders of magnitude less potent on the FAAH, while compounds 31 and 32 were potent FAAH inhibitors (IC50 <20 nM) and over 12-fold selective versus MAGL. The key structural determinants driving the structure–activity relationships were explored by the minimization of the inhibitors inside the active site of both enzymes. 相似文献
15.
Michael K. Ameriks Hui Cai James P. Edwards Damara Gebauer Elizabeth Gleason Yin Gu Lars Karlsson Steven Nguyen Siquan Sun Robin L. Thurmond Jian Zhu 《Bioorganic & medicinal chemistry letters》2009,19(21):6135-6139
Basic lipophilic substituents dramatically improved the cellular potency of a previously disclosed series of pyrazole-based arylalkyne cathepsin S inhibitors. The incorporation of substituted benzylamines in the para position of the arylalkyne maintained enzymatic activity (hCatS IC50 = 80–420 nM) and imparted cellular potency (IC50 = 0.8–4.0 μM). Further refinement of the morpholine portion of the pharmacophore enabled the identification of bicyclic piperidines with enhanced affinity for CatS (IC50 = 10–30 nM) and sub-micromolar cellular potency (JY Ii IC50 = 200–720 nM). 相似文献
16.
Two series of novel acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors containing benzimidazole core structure were synthesized by a four-step reaction pathway starting from 4-fluoro-3-nitrobenzoic acid as the basic compound. The structure of the novel benzimidazoles was characterized and confirmed by the elemental and mass spectral analyses as well as 1H NMR spectroscopic data. Of the 34 novel synthesized compounds, three benzimidazoles revealed AChE inhibition with IC50 < 10 μM. The highest inhibitory activity (IC50 = 5.12 μM for AChE and IC50 = 8.63 μM for BChE) corresponds to the compound 5IIc (ethyl 1-(3-(1H-imidazol-1-yl)propyl)-2-(4-nitrophenyl)-1H-benzo[d]imidazole-5-carboxylate). The relationship between lipophilicity and the chemical structures as well as their limited structure–activity relationship was discussed. 相似文献
17.
Robert J. Cherney John B. Brogan Ruowei Mo Yvonne C. Lo Gengjie Yang Persymphonie B. Miller Peggy A. Scherle Bruce F. Molino Percy H. Carter Carl P. Decicco 《Bioorganic & medicinal chemistry letters》2009,19(3):597-601
A series of trisubstituted cyclohexanes was designed, synthesized and evaluated as CC chemokine receptor 2 (CCR2) antagonists. This led to the identification of two distinct substitution patterns about the cyclohexane ring as potent and selective CCR2 antagonists. Compound 36 exhibited excellent binding (CCR2 IC50 = 2.4 nM) and functional antagonism (calcium flux IC50 = 2.0 nM and chemotaxis IC50 = 5.1 nM). 相似文献
18.
Xiangdong Su Heather A. Halem Mark P. Thomas Cecile Moutrille Michael D. Culler Nigel Vicker Barry V.L. Potter 《Bioorganic & medicinal chemistry》2012,20(21):6394-6402
The modulation of 11β-HSD1 activity with selective inhibitors has beneficial effects on various metabolic disorders including insulin resistance, dyslipidemia and obesity. Here we report the discovery of a series of novel adamantyl carboxamide and acetamide derivatives as selective inhibitors of human 11β-HSD1 in HEK-293 cells transfected with the HSD11B1 gene. Optimization based on an initially identified 11β-HSD1 inhibitor (3) led to the discovery of potent inhibitors with IC50 values in the 100 nM range. These compounds are also highly selective 11β-HSD1 inhibitors with no activity against 11β-HSD2 and 17β-HSD1. Compound 15 (IC50 = 114 nM) with weak inhibitory activity against the key human cytochrome P450 enzymes and moderate stability in incubation with human liver microsomes is worthy of further development. Importantly, compound 41 (IC50 = 280 nM) provides a new lead that incorporates an adamantyl group surrogate and should enable further series diversification. 相似文献
19.
《Bioorganic & medicinal chemistry》2016,24(21):5393-5399
CXCR4 dimerization has been widely demonstrated both biologically and structurally. This paper mainly focused on the development of structure-based dimeric ligands that target CXCL12–CXCR4 interaction and signaling. This study presents the design and synthesis of a series of [PEG]n linked dimeric ligands of CXCR4 based on the knowledge of the homodimeric crystal structure of CXCR4 and our well established platform of chemistry and bioassays for CXCR4. These new ligands include [PEG]n linked homodimeric or heterodimeric peptides consisting of either two DV3-derived moieties (where DV3 is an all-d-amino acid analog of N-terminal modules of 1–10 (V3) residues of vMIP-II) or hybrids of DV3 moieties and CXCL121–8. Among a total of 24 peptide ligands, four antagonists and three agonists showed good CXCR4 binding affinity, with IC50 values of <50 nM and <800 nM, respectively. Chemotaxis and calcium mobilization assays with SUP-T1 cells further identified two promising lead modulators of CXCR4: ligand 4, a [PEG3]2 linked homodimeric DV3, was an effective CXCR4 antagonist (IC50 = 22 nM); and ligand 21, a [PEG3]2 linked heterodimeric DV3–CXCL121–8, was an effective CXCR4 agonist (IC50 = 407 nM). These dimeric CXCR4 modulators represent new molecular probes and therapeutics that effectively modulate CXCL12–CXCR4 interaction and function. 相似文献
20.
Eiki Takahashi Noriyuki Hirano Takashi Nagahara Satoru Yoshikawa Shinobu Momen Hiroshi Yokokawa Ryoji Hayashi 《Bioorganic & medicinal chemistry letters》2013,23(11):3154-3156
We aimed to discover a novel type of transient receptor potential vanilloid 1 (TRPV1) antagonist because such antagonists are possible drug candidates for treating various disorders. We modified the structure of hit compound 7 (human TRPV1 IC50 = 411 nM) and converted its pyrrolidino group to a (hydroxyethyl)methylamino group, which substantially improved inhibitory activity (15d; human TRPV1 IC50 = 33 nM). In addition, 15d ameliorated bladder overactivity in rats in vivo. 相似文献