共查询到20条相似文献,搜索用时 62 毫秒
1.
Josef KA Aimone LD Lyons J Raddatz R Hudkins RL 《Bioorganic & medicinal chemistry letters》2012,22(12):4198-4202
A novel class of benzocinnolinones analogs of irdabisant were designed and synthesized as histamine H3R antagonists/inverse agonists. Modifications to the pyridazinone portion of the core and linker led to the identification of molecules with excellent target potency and selectivity with improved rat pharmacokinetic properties and reduced potential hERG liabilities. 相似文献
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Design, synthesis, and SAR studies of novel and highly active tri-cyclic HIV integrase inhibitors 总被引:1,自引:0,他引:1
Jin H Cai RZ Schacherer L Jabri S Tsiang M Fardis M Chen X Chen JM Kim CU 《Bioorganic & medicinal chemistry letters》2006,16(15):3989-3992
A novel class of tri-cyclic HIV integrase inhibitors were designed based on conformational analysis of 1,6-naphthyridine carboxamide compound L-870810 and docking the designed inhibitor into the active site of our integrase enzyme model. The efficient syntheses of pyrroloquinoline tri-cyclic analogs are described. The SAR studies resulted in the identification of a lead compound that is more potent and more soluble than L-870810. 相似文献
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Martin Di Grandi Matthew Olson Amar S. Prashad Geraldine Bebernitz Amara Luckay Stanley Mullen Yongbo Hu Girija Krishnamurthy Keith Pitts John O’Connell 《Bioorganic & medicinal chemistry letters》2010,20(1):398-402
Two classes of compounds, thiocarbamates 1 and triazoles 2, have been identified as HIV RT RNase H inhibitors using a novel FRET-based HTS assay. The potent analogs in each series exhibited selectivity and were active in cell-based assays. In addition, saturable, 1:1 stoichiometric binding to target was established and time of addition studies were consistent with inhibition of RT-mediated HIV replication. 相似文献
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Eunae Kim 《Nucleosides, nucleotides & nucleic acids》2016,35(3):130-146
Racemic synthesis of novel 2′,5′,5′-trifluoro-apiose nucleoside phosphonic acid analogs were performed as potent antiviral agents. Phosphonation was performed by direct displacement of triflate intermediate with diethyl (lithiodifluoromethyl) phosphonate to give the corresponding (α,α-difluoroalkyl) phosphonate. Condensation successfully proceeded from a glycosyl donor with persilylated bases to yield the nucleoside phosphonate analogs. Deprotection of diethyl phosphonates provided the target nucleoside analogs. An antiviral evaluation of the synthesized compounds against various viruses such as HIV, HSV-1, HSV-2, and HCMV revealed that the pyrimidine analogues have significant anti-HCMV activity. 相似文献
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Scott LM Chen L Daniel KG Brooks WH Guida WC Lawrence HR Sebti SM Lawrence NJ Wu J 《Bioorganic & medicinal chemistry letters》2011,21(2):730-733
Shp2 protein tyrosine phosphate (PTP) is a novel target for anticancer drug discovery. We identified estramustine phosphate as a Shp2 PTP inhibitor from the National Cancer Institute Approved Oncology Drug set. A focused structure-activity relationship study indicated that the 17-phosphate group is required for the Shp2 PTP inhibitor activity of estramustine phosphate. A search for estramustine phosphate analogs led to identification of two triterpenoids, enoxolone, and celastrol, having Shp2 PTP inhibitor activity. With the previously reported PTP1B inhibitor trodusquemine, our study reveals steroids and triterpenoids with negatively charged phosphate, carboxylate, or sulfonate groups as novel pharmacophores of selective PTP inhibitors. 相似文献
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Human immunodeficiency virus type 1 Nef associates with a member of the p21-activated kinase family. 总被引:18,自引:13,他引:5
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Although human immunodeficiency virus (HIV) Nef is essential for the induction of AIDS, its biochemical function has remained an enigma. In this study, HIV Nef protein is shown to associate with a serine-threonine kinase that recognizes histone H4 as a substrate, is serologically related to rat p21-activated kinase (PAK), and is specifically activated by Rac and Cdc42. These characteristics define the Nef-associated kinase as belonging to the PAK family. PAKs initiate kinase cascades in response to environmental stimuli, and their identification as a target of Nef implicates these signaling molecules in HIV pathogenesis and provides a novel target for clinical intervention. 相似文献
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Abstract A strategy based on the use of (trifluoromethyl) trimethylsilane for introduction of the trifluoromethyl group at the C-4 of ribose has been developed and utilized in the synthesis of various novel 4′-trifluoromethylated nucleoside analogs. Screening of these analogs against HIV did not reveal significant biological activity. 相似文献
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Gore VK Ma VV Tamir R Gavva NR Treanor JJ Norman MH 《Bioorganic & medicinal chemistry letters》2007,17(21):5825-5830
A novel series of 4,5-biarylimidazoles as TRPV1 antagonists were designed based on the previously reported 4,6-disubstituted benzimidazole series. The analogs were evaluated for their ability to block capsaicin- or acid-induced calcium influx in TRPV1-expressing CHO cells. These studies led to the identification of a highly potent and orally bioavailable TRPV1 antagonist, imidazole 33. 相似文献
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Synthesis and antiviral activity of P1' arylsulfonamide azacyclic urea HIV protease inhibitors 总被引:2,自引:0,他引:2
Huang PP Randolph JT Klein LL Vasavanonda S Dekhtyar T Stoll VS Kempf DJ 《Bioorganic & medicinal chemistry letters》2004,14(15):4075-4078
A series of novel azacyclic urea HIV protease inhibitors bearing a benzenesulfonamide group at P1' were synthesized utilizing a parallel synthesis method. Structural studies of early analogs bound in the enzyme active site were used to design more potent inhibitors. The effects of substituting the P1' benzenesulfonyl group on antiviral activity and protein binding are described. 相似文献
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John P Pribis Yousef Al-Abed Huan Yang Domokos Gero Hongbo Xu Marcelo F Montenegro Eileen M Bauer Sodam Kim Sangeeta S Chavan Changchun Cai Tunliang Li Petra Szoleczky Csaba Szabo Kevin J Tracey Timothy R Billiar 《Molecular medicine (Cambridge, Mass.)》2015,21(1):749-757
Extracellular high-mobility group box 1 (HMGB1) (disulfide form), via activation of toll-like receptor 4 (TLR4)-dependent signaling, is a strong driver of pathologic inflammation in both acute and chronic conditions. Identification of selective inhibitors of HMGB1-TLR4 signaling could offer novel therapies that selectively target proximal endogenous activators of inflammation. A cell-based screening strategy led us to identify first generation HIV-protease inhibitors (PI) as potential inhibitors of HMGB1-TLR4 driven cytokine production. Here we report that the first-generation HIV-PI saquinavir (SQV), as well as a newly identified mammalian protease inhibitor STO33438 (334), potently block disulfide HMGB1-induced TLR4 activation, as assayed by the production of TNF-α by human monocyte-derived macrophages (THP-1). We further report on the identification of mammalian cathepsin V, a protease, as a novel target of these inhibitors. Cellular as well as recombinant protein studies show that the mechanism of action involves a direct interaction between cathepsin V with TLR4 and its adaptor protein MyD88. Treatment with SQV, 334 or the known cathepsin inhibitor SID26681509 (SID) significantly improved survival in murine models of sepsis and reduced liver damage following warm liver ischemia/reperfusion (I/R) models, both characterized by strong HMGB1-TLR4 driven pathology. The current study demonstrates a novel role for cathepsin V in TLR4 signaling and implicates cathepsin V as a novel target for first-generation HIV-PI compounds. The identification of cathepsin V as a target to block HMGB1-TLR4-driven inflammation could allow for a rapid transition of the discovery from the bench to the bedside. Disulfide HMGB1 drives pathologic inflammation in many models by activating signaling through TLR4. Cell-based screening identified the mammalian protease cathepsin V as a novel therapeutic target to inhibit TLR4-mediated inflammation induced by extracellular HMGB1 (disulfide form). We identified two protease inhibitors (PIs) that block cathepsin V and thereby inhibit disulfide HMGB1-induced TLR4 activation: saquinavir (SQV), a first-generation PI targeting viral HIV protease and STO33438 (334), targeting mammalian proteases. We discovered that cathepsin V binds TLR4 under basal and HMGB1-stimulated conditions, but dissociates in the presence of SQV over time. Thus cathepsin V is a novel target for first-generation HIV PIs and represents a potential therapeutic target of pathologic inflammation. 相似文献
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A series of nucleobase-modified analogs of the anticancer compounds 3'-C-ethynyluridine (EUrd) and 3'-C-ethynylcytidine (ECyd) were designed to overcome the strict substrate specificity of the activating uridine-cytidine kinase. EUrd, ECyd and target nucleosides were obtained using a short convergent synthetic route utilizing diacetone-alpha-D-glucose as starting material. 5-Iodo-substituted EUrd was the most potent inhibitor among the novel nucleobase-modified analogs in in vitro assays against human adenocarcinoma breast and prostate cancer cells with IC50 values down to 35 nM. 相似文献
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Charles A. Flentge John T. Randolph Peggy P. Huang Larry L. Klein Kennan C. Marsh John E. Harlan Dale J. Kempf 《Bioorganic & medicinal chemistry letters》2009,19(18):5444-5448
The HIV protease inhibitor ritonavir (RTV) is also a potent inhibitor of the metabolizing enzyme cytochrome P450 3A (CYP3A) and is clinically useful in HIV therapy in its ability to enhance human plasma levels of other HIV protease inhibitors (PIs). A novel series of CYP3A inhibitors was designed around the structural elements of RTV believed to be important to CYP3A inhibition, with general design features being the attachment of groups that mimic the P2–P3 segment of RTV to a soluble core. Several analogs were found to strongly enhance plasma levels of lopinavir (LPV), including 8, which compares favorably with RTV in the same model. Interestingly, an inverse correlation between in vitro inhibition of CYP3A and elevation of LPV was observed. The compounds described in this study may be useful for enhancing the pharmacokinetics of drugs that are metabolized by CYP3A. 相似文献
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François Bilodeau Murray D. Bailey Punit K. Bhardwaj Josée Bordeleau Pat Forgione Michel Garneau Elise Ghiro Vida Gorys Ted Halmos Eric S. Jolicoeur Mélissa Leblanc Christopher T. Lemke Julie Naud Jeff O’Meara Peter W. White Montse Llinàs-Brunet 《Bioorganic & medicinal chemistry letters》2013,23(14):4267-4271
In this report we describe the synthesis and evaluation of diverse 4-arylproline analogs as HCV NS3 protease inhibitors. Introduction of this novel P2 moiety opened up new SAR and, in combination with a synthetic approach providing a versatile handle, allowed for efficient exploitation of this novel series of NS3 protease inhibitors. Multiple structural modifications of the aryl group at the 4-proline, guided by structural analysis, led to the identification of analogs which were very potent in both enzymatic and cell based assays. The impact of this systematic SAR on different drug properties is reported. 相似文献
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We review the evidence that the function of the SLC25A19 gene product, previously identified as the mitochondrial deoxyribonucleotide carrier (DNC), is actually the transport of thiamine pyrophosphate. This evidence comes from enzyme kinetics, homologous yeast protein alignments, gene knockout studies, and clinical samples from Amish Microcephaly patients. This diverse body of evidence consistently points to the conclusion that SLC25A19 is not the true mitochondrial DNC gene. The identification of the correct mitochondrial DNC is important for research on the genetic diseases of mitochondrial DNA maintenance and the toxicity experienced by many HIV patients undergoing antiretroviral therapy involving nucleoside analogs. 相似文献
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A series of analogs of the potent HIV-1 integrase (HIV IN) inhibitor chicoric acid (CA) was designed with the intention of ameliorating some of the parent natural product's undesirable properties, in particular its toxicity, instability, and poor membrane permeability. More than 70 analogs were synthesized and assayed for three types of activity: (1) the ability to inhibit 3'-end processing and strand transfer reactions using recombinant HIV IN in vitro, (2) toxicity against the CD4+ lymphoblastoid cell line, MT2, and (3) anti-HIV activity against HIV(LAI). CA analogs lacking one of the carboxyl groups of CA and with 3,4,5-trihydroxycinnamoyl sidechains in place of the caffeoyl group of CA exhibited the most potent inhibition of HIV replication and end-processing activity. Galloyl-substituted derivatives also displayed very potent in vitro and in vivo activities, in most cases exceeding the inhibitory effects of CA itself. Conversely, analogous monocarboxy caffeoyl analogs exhibited only modest inhibition, while the corresponding 3,4-dihydroxybenzoyl-substituted compounds were devoid of activity. 相似文献
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Xie Y Raffo A Ichise M Deng S Harris PE Landry DW 《Bioorganic & medicinal chemistry letters》2008,18(18):5111-5114
Vesicular monoamine transporter type 2 (VMAT2) is a newly emerging target for both diagnostic and therapeutic applications in diabetes mellitus. In pursuit of novel VMAT2 antagonists, we identified a potent hypoglycemic agent with a novel dihydropyridone scaffold. Several analogs were designed and synthesized. A preliminary structure activity relationship (SAR) showed that the dihydropyridone scaffold is required for the activity. 相似文献