Abstract:
:A hybrid approach was applied for the design of an inhibitor of trypsin-like serine proteases. Compound 16 [(R,R)- and (R,S)-diphenyl (4-(1-(4-amidinobenzylamino)-1-oxo-3-phenylpropan-2-ylcarbamoyl)phenylamino)(4-amidinophenyl)methylphosphonate hydrochloride], prepared in a convergent synthetic procedure, possesses a phosphonate warhead prone to react with the active site serine residue in a covalent, irreversible manner. Each of the two benzamidine moieties of 16 can potentially be accommodated in the S1 pocket of the target enzyme, but only the benzamidine close to the phosphonate group would then promote an irreversible interaction. The Janus-faced inhibitor 16 was evaluated against several serine proteases and caused a pronounced inactivation of human thrombin with a second-order rate constant (kinac /Ki) of 59 500 M(-1) s(-1). With human matriptase, 16 showed preference for a reversible mode of inhibition (IC50 =2.6 μM) as indicated by linear progress curves and enzyme reactivation.
journal_name
ChemMedChemjournal_title
ChemMedChemauthors
Häußler D,Scheidt T,Stirnberg M,Steinmetzer T,Gütschow Mdoi
10.1002/cmdc.201500319subject
Has Abstractpub_date
2015-10-01 00:00:00pages
1641-6issue
10eissn
1860-7179issn
1860-7187journal_volume
10pub_type
杂志文章相关文献
ChemMedChem文献大全abstract::The three databases of PubChem, ChemSpider, and UniChem capture the majority of open chemical structure records with February 2018 totals of 95, 63, and 154 million, respectively. Collectively, they constitute a massively enabling resource for cheminformatics, chemical biology, and drug discovery. As meta-portals, the...
journal_title:ChemMedChem
pub_type: 杂志文章,评审
doi:10.1002/cmdc.201700724
更新日期:2018-03-20 00:00:00
abstract::Despite significant advances made in the last decade in the understanding of molecular mechanisms of sepsis and in the development of clinically relevant therapies, sepsis remains the leading cause of mortality in intensive care units with increasing incidence worldwide. Toll-like receptor 4 (TLR4)-a transmembrane pat...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201800505
更新日期:2018-11-06 00:00:00
abstract::The disruption of aberrant protein-protein interactions (PPIs) with synthetic agents remains a challenging goal in contemporary medicinal chemistry but some progress has been made. One such dysregulated PPI is that between the anti-apoptotic Bcl-2 proteins, including myeloid cell leukemia-1 (Mcl-1), and the α-helical ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201500461
更新日期:2016-04-19 00:00:00
abstract::Dopamine (DA) D(3) receptor antagonism might play a significant role in different therapeutic areas. A high number of preclinical studies on DA D(3) receptor antagonists have shown efficacy in animal models of Parkinson's disease, schizophrenia and drug dependence. This Review covers the activities of medicinal chemis...
journal_title:ChemMedChem
pub_type: 杂志文章,评审
doi:10.1002/cmdc.201000538
更新日期:2011-07-04 00:00:00
abstract::The natural product piperlonguminine (PL) has been shown to exert potential anticancer activity against several types of cancer via elevation of reactive oxidative species (ROS). However, the application of PL has been limited due to its poor water solubility and moderate activity. To improve PL's potency, we designed...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.202000660
更新日期:2020-10-21 00:00:00
abstract::ABC, it's easy as 1 2 3! Bioisosteric replacement of the anilide core by an indole moiety considerably increased stability and gave potent and selective ABCG2 (BCRP) inhibitors. Some compounds are superior to the reference substances fumitremorgin C and Ko143 in terms of potency and efficacy and are the most potent AB...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201300319
更新日期:2013-11-01 00:00:00
abstract::A new class of imidazo[2,1-b]thiazole chalcone derivatives were synthesized and evaluated for their anticancer activity. These chalcone derivatives show promising activity, with log GI(50) values ranging from -7.51 to -4.00. The detailed biological aspects of these derivatives toward the MCF-7 cell line were studied. ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201000346
更新日期:2010-11-08 00:00:00
abstract::The NLRP3 inflammasome is an important regulator of the sterile inflammatory response, and its activation by host-derived sterile molecules leads to the intracellular activation of caspase-1, processing of the pro-inflammatory cytokines interleukin-1β (IL-1β)/IL-18, and pyroptotic cell death. Inappropriate activation ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201700731
更新日期:2018-02-20 00:00:00
abstract::For (64) Cu radiolabeling of biomolecules to be used as in vivo positron emission tomography (PET) imaging agents, various chelators are commonly applied. It has not yet been determined which of the most potent chelators--NODA-GA ((1,4,7-triazacyclononane-4,7-diyl)diacetic acid-1-glutaric acid), CB-TE2A (2,2'-(1,4,8,1...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201500132
更新日期:2015-07-01 00:00:00
abstract::Aberrant WNT pathway activation, leading to nuclear accumulation of β-catenin, is a key oncogenic driver event. Mutations in the tumor suppressor gene APC lead to impaired proteasomal degradation of β-catenin and subsequent nuclear translocation. Restoring cellular degradation of β-catenin represents a potential thera...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.202000839
更新日期:2020-12-04 00:00:00
abstract::Despite improvements in the treatment and prevention of cancer, the number of new diagnoses continues to rise; this has fuelled substantial interest in the development of new and effective chemotherapeutic agents. Compounds of the triazene class, such as dacarbazine, have been used in the clinical management of many c...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201100027
更新日期:2011-07-04 00:00:00
abstract::LSD1 is a lysine demethylase highly involved in initiation and development of cancer. To design highly effective covalent inhibitors, a strategy is to fill its large catalytic cleft by designing tranylcypromine (TCP) analogs decorated with long, hindered substituents. We prepared three series of TCP analogs, carrying ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201900730
更新日期:2020-04-03 00:00:00
abstract::Uropathogenic E. coli (UPEC) employ the mannose-binding adhesin FimH to colonize the bladder epithelium during urinary tract infection (UTI). Previously reported FimH antagonists exhibit good potency and efficacy, but low bioavailability and a short half-life in vivo. In a rational design strategy, we obtained an X-ra...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201600006
更新日期:2016-02-17 00:00:00
abstract::A series of novel (R)/(S)-7-(3-alkoxyimino-2-aminomethyl-1-azetidinyl)fluoroquinolone derivatives were synthesized and evaluated for their in vitro antibacterial activity against representative strains. Our results reveal that 12 of the target compounds generally show better activity (MIC: <0.008-0.5 μg mL(-1)) agains...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201200210
更新日期:2012-07-01 00:00:00
abstract::Better control of postprandial hyperglycemia can be achieved by delaying the absorption of glucose resulting from carbohydrate digestion. Because α-amylase initiates the hydrolysis of polysaccharides, the design of α-amylase inhibitors can lead to the development of new treatments for metabolic disorders such as type ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201600427
更新日期:2016-11-07 00:00:00
abstract::PH-797804 ((aS)-3-{3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl}-N,4-dimethylbenzamde) is a diarylpyridinone inhibitor of p38 mitogen-activated protein (MAP) kinase derived from a racemic mixture as the more potent atropisomer (aS), first proposed by molecular modeling and subsequently confirmed ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201100439
更新日期:2012-02-06 00:00:00
abstract::P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) is a major obstacle for successful cancer chemotherapy. Based on our previous study, 17 novel compounds with the 6,7-dimethoxy-2-{2-[4-(1H-1,2,3-triazol-1-yl)phenyl]ethyl}-1,2,3,4-tetrahydroisoquinoline scaffold were designed and synthesized. Among them, 2-[(1-...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201402463
更新日期:2015-02-01 00:00:00
abstract::Protein-protein and protein-carbohydrate interactions as a means to target the cell surface for therapeutic applications have been extensively investigated. However, carbohydrate-carbohydrate interactions (CCIs) have largely been overlooked. Here, we investigate the concept of CCI-mediated drug delivery. Lactose-funct...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201500046
更新日期:2015-05-01 00:00:00
abstract::Soluble guanylate cyclase (sGC) is a key signal-transduction enzyme activated by nitric oxide (NO). Impairments of the NO-sGC signaling pathway have been implicated in the pathogenesis of cardiovascular and other diseases. Direct stimulation of sGC represents a promising therapeutic strategy particularly for the treat...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200900014
更新日期:2009-05-01 00:00:00
abstract::Cellular chaperones that belong to the heat-shock protein 90 (Hsp90) family are a prerequisite for successful viral propagation for most viruses. The hepatitis C virus (HCV) uses Hsp90 for maturation, folding, and modification of viral proteins. Based on our previous discovery that marine alkaloid analogues with a 4,5...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201800724
更新日期:2019-02-05 00:00:00
abstract::The Pathogen Box is a 400-strong collection of drug-like compounds, selected for their potential against several of the world's most important neglected tropical diseases, including trypanosomiasis, leishmaniasis, cryptosporidiosis, toxoplasmosis, filariasis, schistosomiasis, dengue virus and trichuriasis, in addition...
journal_title:ChemMedChem
pub_type: 杂志文章,评审
doi:10.1002/cmdc.201800755
更新日期:2019-02-19 00:00:00
abstract::Intraoperative imaging technologies recently entered the operating room, and their implementation is revolutionizing how physicians plan, monitor, and perform surgical interventions. In this work, we present a novel surgical imaging reporter system: intraoperative chemiluminescence imaging (ICI). To this end, we have ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201600301
更新日期:2016-09-20 00:00:00
abstract::The Eph-ephrin system, including the EphA2 receptor and the ephrinA1 ligand, plays a critical role in tumor and vascular functions during carcinogenesis. We previously identified (3α,5β)-3-hydroxycholan-24-oic acid (lithocholic acid) as an Eph-ephrin antagonist that is able to inhibit EphA2 receptor activation; it is ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201200102
更新日期:2012-06-01 00:00:00
abstract::Natural products containing the α,β-unsaturated δ-lactone skeleton have been shown to possess a variety of biological activities. The natural product (-)-tarchonanthuslactone (1) possessing this privileged scaffold is a popular synthetic target, but its biological activity remains underexplored. Herein, the total synt...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201500246
更新日期:2015-10-01 00:00:00
abstract::The polyether ionophore salinomycin (SAL) has captured much interest because of its potent activity against cancer cells and cancer stem cells. Our previous studies have indicated that C1/C20 double-modification of SAL is a useful strategy to generate diverse agents with promising biological activity profiles. Thus, h...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201900593
更新日期:2020-01-17 00:00:00
abstract::Tau-tubulin kinase 1 (TTBK1) is a serine/threonine/tyrosine kinase that putatively phosphorylates residues including S422 in tau protein. Hyperphosphorylation of tau protein is the primary cause of tau pathology and neuronal death associated with Alzheimer's disease. A library of 12 truncation variants comprising the ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201300274
更新日期:2013-11-01 00:00:00
abstract::Discovered as a modulator of the toxic response to environmental pollutants, aryl hydrocarbon receptor (AhR) has recently gained attention for its involvement in various physiological and pathological pathways. AhR is a ligand-dependent transcription factor activated by a large array of chemical compounds, which inclu...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201700669
更新日期:2018-02-06 00:00:00
abstract::The histone deacetylase (HDAC) family is a promising drug target class owing to the importance of these enzymes in a variety of cellular processes. Docking studies were conducted to identify novel HDAC inhibitors. Subtle modifications in the recognition domain were introduced into a series of chlamydocin analogues, an...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201300372
更新日期:2014-03-01 00:00:00
abstract::Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) is a small molecule with potent anticancer activity. Like other 1,4-naphthoquinones, it exhibits electrophilic reactivity towards biological nucleophiles. We demonstrate that plumbagin and structurally related 1,4-naphthoquinones with at least one unsubstituted quinoid...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.202000157
更新日期:2020-07-20 00:00:00
abstract::Here we report the synthesis of a number of compounds structurally related to arginine methyltransferase inhibitor 1 (AMI-1). The structural alterations that we made included: 1) the substitution of the sulfonic groups with the bioisosteric carboxylic groups; 2) the replacement of the ureidic function with a bis-amidi...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200900459
更新日期:2010-03-01 00:00:00