共查询到20条相似文献,搜索用时 15 毫秒
1.
《Bioorganic & medicinal chemistry》2016,24(2):201-206
Human immunodeficiency virus type 1 (HIV-1), the pathogen of acquired immunodeficiency syndrome (AIDS), causes about 2 million people to death every year. Fusion inhibitors targeted the envelope protein (gp41) represent a novel and alternative approach for anti-AIDS therapy, which terminates the HIV-1 life cycle at an early stage. Using CP621-652 as a template, a series of peptides were designed, synthesized and evaluated in vitro assays. An interesting phenomenon was found that the substitution of hydrophobic residues at solvent accessible sites could increase the anti-HIV activity when the C-terminal sequence was extended with an enough numbers of amino acids. After the active peptides was synthesized and evaluated, peptide 8 showed the best anti-HIV-1 IIIB whole cell activity (MAGI IC50 = 53.02 nM). Further study indicated that peptide 8 bound with the gp41 NHR helix, and then blocked the conformation of 6-helix, thus inhibited virus–cell membrane fusion. The results would be helpful for the design of peptide fusion inhibitors against HIV-1 infection. 相似文献
2.
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
3.
Janet Gunzner-Toste Guiling Zhao Paul Bauer Timm Baumeister Alexandre J. Buckmelter Maureen Caligiuri Karl H. Clodfelter Bang Fu Bingsong Han Yen-Ching Ho Nikolai Kley Xiaorong Liang Bianca M. Liederer Jian Lin Sophie Mukadam Thomas O’Brien Angela Oh Dominic J. Reynolds Peter S. Dragovich 《Bioorganic & medicinal chemistry letters》2013,23(12):3531-3538
Potent, reversible inhibition of the cytochrome P450 CYP2C9 isoform was observed in a series of urea-containing nicotinamide phosphoribosyltransferase (NAMPT) inhibitors. This unwanted property was successfully removed from the described inhibitors through a combination of structure-based design and medicinal chemistry activities. An optimized compound which did not inhibit CYP2C9 exhibited potent anti-NAMPT activity (17; BC NAMPT IC50 = 3 nM; A2780 antiproliferative IC50 = 70 nM), good mouse PK properties, and was efficacious in an A2780 mouse xenograft model. The crystal structure of this compound in complex with the NAMPT protein is also described. 相似文献
4.
《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
5.
Arun K. Ghosh W. Sean Fyvie Margherita Brindisi Melinda Steffey Johnson Agniswamy Yuan-Fang Wang Manabu Aoki Masayuki Amano Irene T. Weber Hiroaki Mitsuya 《Bioorganic & medicinal chemistry letters》2017,27(21):4925-4931
Design, synthesis, and evaluation of a new class of HIV-1 protease inhibitors containing diverse flexible macrocyclic P1′-P2′ tethers are reported. Inhibitor 5a with a pyrrolidinone-derived macrocycle exhibited favorable enzyme inhibitory and antiviral activity (Ki = 13.2 nM, IC50 = 22 nM). Further incorporation of heteroatoms in the macrocyclic skeleton provided macrocyclic inhibitors 5m and 5o. These compounds showed excellent HIV-1 protease inhibitory (Ki = 62 pM and 14 pM, respectively) and antiviral activity (IC50 = 5.3 nM and 2.0 nM, respectively). Inhibitor 5o also remained highly potent against a DRV-resistant HIV-1 variant. 相似文献
6.
Tetsuo Takayama Hiroki Umemiya Hideaki Amada Tetsuya Yabuuchi Takeshi Koami Fumiyasu Shiozawa Yusuke Oka Akiko Takaoka Akie Yamaguchi Mayumi Endo Masakazu Sato 《Bioorganic & medicinal chemistry letters》2010,20(1):112-116
We have identified a novel series of ring-fused pyrazole derivatives as lymphocyte-specific kinase (Lck) inhibitors. The most potent analogs exhibited good enzyme inhibitory activity (IC50s <1 nM) as well as excellent cellular activity against mixed lymphocyte reaction (MLR) (IC50s <1 nM). 相似文献
7.
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
8.
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
9.
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
10.
Mauricio Mora-Pale Michel Weïwer Jingjing Yu Robert J. Linhardt Jonathan S. Dordick 《Bioorganic & medicinal chemistry》2009,17(14):5146-5152
Enzymatic oxidation of apocynin, which may mimic in vivo metabolism, affords a large number of oligomers (apocynin oxidation products, AOP) that inhibit vascular NADPH oxidase. In vitro studies of NADPH oxidase activity were performed to identify active inhibitors, resulting in a trimer hydroxylated quinone (IIIHyQ) that inhibited NADPH oxidase with an IC50 = 31 nM. Apocynin itself possessed minimal inhibitory activity. NADPH oxidase is believed to be inhibited through prevention of the interaction between two NADPH oxidase subunits, p47phox and p22phox. To that end, while apocynin was unable to block the interaction of his-tagged p47phox with a surface immobilized biotinylated p22phox peptide, the IIIHyQ product strongly interfered with this interaction (apparent IC50 = 1.6 μM). These results provide evidence that peroxidase-generated AOP, which consist of oligomeric phenols and quinones, inhibit critical interactions that are involved in the assembly and activation of human vascular NADPH oxidase. 相似文献
11.
Yan Shi Chi Li Stephen P. O’Connor Jing Zhang Mengxiao Shi Sharon N. Bisaha Ying Wang Doree Sitkoff Andrew T. Pudzianowski Christine Huang Herbert E. Klei Kevin Kish Joseph Yanchunas Eddie C.-K. Liu Karen S. Hartl Steve M. Seiler Thomas E. Steinbacher William A. Schumacher Karnail S. Atwal Philip D. Stein 《Bioorganic & medicinal chemistry letters》2009,19(24):6882-6889
We report the design and synthesis of a novel class of N,N′-disubstituted aroylguanidine-based lactam derivatives as potent and orally active FXa inhibitors. The structure–activity relationships (SAR) investigation led to the discovery of the nicotinoyl guanidine 22 as a potent FXa inhibitor (FXa IC50 = 4 nM, EC2×PT = 7 μM). However, the potent CYP3A4 inhibition activity (IC50 = 0.3 μM) of 22 precluded its further development. Detailed analysis of the X-ray crystal structure of compound 22 bound to FXa indicated that the substituent at the 6-position of the nicotinoyl group of 22 would be solvent-exposed, suggesting that efforts to attenuate the unwanted CYP activity could focus at this position without affecting FXa potency significantly. Further SAR studies on the 6-substituted nicotinoyl guanidines resulted in the discovery of 6-(dimethylcarbamoyl) nicotinoyl guanidine 36 (BMS-344577, IC50 = 9 nM, EC2×PT = 2.5 μM), which was found to be a selective, orally efficacious FXa inhibitor with an excellent in vitro liability profile, favorable pharmacokinetics and pharmacodynamics in animal models. 相似文献
12.
Michael K. Ameriks Scott D. Bembenek Matthew T. Burdett Ingrid C. Choong James P. Edwards Damara Gebauer Yin Gu Lars Karlsson Hans E. Purkey Bart L. Staker Siquan Sun Robin L. Thurmond Jian Zhu 《Bioorganic & medicinal chemistry letters》2010,20(14):4060-4064
A pyridazin-4-one fragment 4 (hCatS IC50 = 170 μM) discovered through Tethering was modeled into cathepsin S and predicted to overlap in S2 with the tetrahydropyridinepyrazole core of a previously disclosed series of CatS inhibitors. This fragment served as a template to design pyridazin-3-one 12 (hCatS IC50 = 430 nM), which also incorporates P3 and P5 binding elements. A crystal structure of 12 bound to Cys25Ser CatS led to the synthesis of the potent diazinone isomers 22 (hCatS IC50 = 60 nM) and 27 (hCatS IC50 = 40 nM). 相似文献
13.
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
14.
《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
15.
Ashok Kumar Kumkum Srivastava S. Raja Kumar S.K. Puri Prem M.S. Chauhan 《Bioorganic & medicinal chemistry letters》2009,19(24):6996-6999
There is challenge and urgency to synthesize cost-effective chemotherapeutic agents for treatment of malaria after the widespread development of resistance to CQ. In the present study, we synthesized a new series of hybrid 9-anilinoacridine triazines using the cheap chemicals 6,9-dichloro-2-methoxy acridine and cyanuric chloride. The series of new hybrid 9-anilinoacridine triazines were evaluated in vitro for their antimalarial activity against CQ-sensitive 3D7 strain of Plasmodium falciparum and their cytotoxicity were determined on VERO cell line. Of the evaluated compounds, two compounds 17 (IC50 = 4.21 nM) and 22 (IC50 = 4.27 nM) displayed two times higher potency than CQ (IC50 = 8.15 nM). Most of the compounds showed fairly high selectivity index. The compounds 13 and 29 displayed >96.59% and 98.73% suppression, respectively, orally against N-67 strain of Plasmodium yoelii in swiss mice at dose 100 mg/kg for four days. 相似文献
16.
Daniel P. Mould Ulf Bremberg Allan M. Jordan Matthis Geitmann Alison E. McGonagle Tim C.P. Somervaille Gary J. Spencer Donald J. Ogilvie 《Bioorganic & medicinal chemistry letters》2017,27(20):4755-4759
As part of our ongoing efforts to develop reversible inhibitors of LSD1, we identified a series of 4-(pyrrolidin-3-yl)benzonitrile derivatives that act as successful scaffold-hops of the literature inhibitor GSK-690. The most active compound, 21g, demonstrated a Kd value of 22 nM and a biochemical IC50 of 57 nM. In addition, this compound displayed improved selectivity over the hERG ion channel compared to GSK-690, and no activity against the related enzymes MAO-A and B. In human THP-1 acute myeloid leukaemia cells, 21g was found to increase the expression of the surrogate cellular biomarker CD86. This work further demonstrates the versatility of scaffold-hopping as a method to develop structurally diverse, potent inhibitors of LSD1. 相似文献
17.
Maria João Matos Dolores Viña Patricia Janeiro Fernanda Borges Lourdes Santana Eugenio Uriarte 《Bioorganic & medicinal chemistry letters》2010,20(17):5157-5160
With the aim to find out the structural features for the MAO inhibitory activity and selectivity, in the present communication we report the synthesis and pharmacological evaluation of a new series of bromo-6-methyl-3-phenylcoumarin derivatives (with bromo atom in both different benzene rings of the skeleton) with and without different number of methoxy substituent at the 3-phenyl ring. The methoxy substituents were introduced, in this new scaffold, in the meta and/or para positions of the 3-phenyl ring. The synthesized compounds 3–7 were evaluated as MAO-A and B inhibitors using R-(?)-deprenyl (selegiline) and iproniazide as reference inhibitors, showing, most of them, MAO-B inhibitory activities in the low nanomolar range. Compounds 4 (IC50 = 11.05 nM), 5 (IC50 = 3.23 nM) and 6 (IC50 = 7.12 nM) show higher activity than selegiline (IC50 = 19.60 nM) and higher MAO-B selectivity, with more than 9050-fold, 30,960-fold and 14,045-fold inhibition levels, with respect to the MAO-A isoform. 相似文献
18.
Bin Sun Juma Hoshino Katie Jermihov Laura Marler John M. Pezzuto Andrew D. Mesecar Mark Cushman 《Bioorganic & medicinal chemistry》2010,18(14):5352-5366
A series of new resveratrol analogues were designed and synthesized and their inhibitory activities against aromatase were evaluated. The crystal structure of human aromatase (PDB 3eqm) was used to rationalize the mechanism of action of the aromatase inhibitor 32 (IC50 0.59 μM) through docking, molecular mechanics energy minimization, and computer graphics molecular modeling, and the information was utilized to design several very potent inhibitors, including compounds 82 (IC50 70 nM) and 84 (IC50 36 nM). The aromatase inhibitory activities of these compounds are much more potent than that for the lead compound resveratrol, which has an IC50 of 80 μM. In addition to aromatase inhibitory activity, compounds 32 and 44 also displayed potent QR2 inhibitory activity (IC50 1.7 μM and 0.27 μM, respectively) and the high-resolution X-ray structures of QR2 in complex with these two compounds provide insight into their mechanism of QR2 inhibition. The aromatase and quinone reductase inhibitors resulting from these studies have potential value in the treatment and prevention of cancer. 相似文献
19.
《Bioorganic & medicinal chemistry》2014,22(15):3871-3878
Recently inhibition of ROS1 kinase has proven to be a promising strategy for several indications such as glioblastoma, non-small cell lung cancer (NSCLC), and cholangiocarcinoma. Our team reported trisubstituted pyrazole-based ROS1 inhibitors by which two inhibitors showed good IC50 values in enzyme-based screening. To develop more advanced ROS1 inhibitors through SAR this trisubstituted pyrazole-based scaffold has been built. Consequently, 16 compounds have been designed, synthesized and shown potent IC50 values in the enzymatic assay, which are from 13.6 to 283 nM. Molecular modeling studies explain how these ROS1 kinase inhibitors revealed effectively the key interactions with ROS1 ATP binding site. Among these compounds, compound 9a (IC50 = 13.6 nM) has exerted 5 fold potency than crizotinib and exhibited high degree of selectivity (selectivity score value = 0.028) representing the number of non-mutant kinases with biological activity over 90% at 10 μM. 相似文献
20.
Anand Balupuri Dae-Yon Lee Myeong Hwi Lee Sangeun Chae Eunmi Jung Yunki Kim Jeonghee Ryu Nam Sook Kang 《Bioorganic & medicinal chemistry letters》2017,27(17):4156-4164
The autotaxin-lysophophatidic acid (ATX-LPA) signaling pathway is involved in several human diseases such as cancer, autoimmune diseases, inflammatory diseases neurodegenerative diseases and fibrotic diseases. Herein, a series of 4-phenyl-thiazole based compounds was designed and synthesized. Compounds were evaluated for their ATX inhibitory activity using FS-3 and human plasma assays. In the FS-3 assay, compounds 20 and 21 significantly inhibited the ATX at low nanomolar level (IC50 = 2.99 and 2.19 nM, respectively). Inhibitory activity of 21 was found to be slightly better than PF-8380 (IC50 = 2.80 nM), which is one of the most potent ATX inhibitors reported till date. Furthermore, 21 displayed higher potency (IC50 = 14.99 nM) than the first clinical ATX inhibitor, GLPG1690 (IC50 = 242.00 nM) in the human plasma assay. Molecular docking studies were carried out to explore the binding pattern of newly synthesized compounds within active site of ATX. Docking studies suggested the putative binding mode of the novel compounds. Good ATX inhibitory activity of 21 was attributed to the hydrogen bonding interactions with Asn230, Trp275 and active site water molecules; electrostatic interaction with catalytic zinc ion and hydrophobic interactions with amino acids of the hydrophobic pocket. 相似文献