当前位置： SCI文献检索 > JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > Potent fibrinolysis inhibitor discovered by shape and electrostatic complementarity to the drug tranexamic acid.

Potent fibrinolysis inhibitor discovered by shape and electrostatic complementarity to the drug tranexamic acid.

Abstract：

:Protein-protein interfaces provide an important class of drug targets currently receiving increased attention. The typical design strategy to inhibit protein-protein interactions usually involves large molecules such as peptides and macrocycles. One exception is tranexamic acid (TXA), which, as a lysine mimetic, inhibits binding of plasminogen to fibrin. However, the daily dose of TXA is high due to its modest potency and pharmacokinetic properties. In this study, we report a computational approach, where the focus was on finding electrostatic potential similarities to TXA. Coupling this computational technique with a high-quality low-throughput screen identified 5-(4-piperidyl)-3-isoxazolol (4-PIOL) as a potent plasminogen binding inhibitor with the potential for the treatment of various bleeding disorders. Remarkably, 4-PIOL was found to be more than four times as potent as the drug TXA.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Boström J,Grant JA,Fjellström O,Thelin A,Gustafsson D

doi

10.1021/jm301818g

subject

Has Abstract

pub_date

2013-04-25 00:00:00

pages

3273-80

issue

8

eissn

0022-2623

issn

1520-4804

journal_volume

56

pub_type

杂志文章

相关文献

JOURNAL OF MEDICINAL CHEMISTRY文献大全
  • N1-substituent effects in the selective delivery of polyamine conjugates into cells containing active polyamine transporters.

    abstract：:Several N(1)-arylalkylpolyamines containing various aromatic ring systems were synthesized as their respective HCl salts. The N(1)-substituents evaluated ranged in size from N(1)-benzyl, N(1)-naphthalen-1-ylmethyl, N(1)-2-(naphthalen-1-yl)ethyl, N(1)-3-(naphthalen-1-yl)propyl, N(1)-anthracen-9-ylmethyl, N(1)-2-(anthra...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm0497040

    authors： Gardner RA,Delcros JG,Konate F,Breitbeil F 3rd,Martin B,Sigman M,Huang M,Phanstiel O 4th

    更新日期：2004-11-18 00:00:00

  • Probing the cysteine-34 position of endogenous serum albumin with thiol-binding doxorubicin derivatives. Improved efficacy of an acid-sensitive doxorubicin derivative with specific albumin-binding properties compared to that of the parent compound.

    abstract：:We have recently proposed a macromolecular prodrug strategy for improved cancer chemotherapy based on two features (Kratz, F.; et al. J. Med. Chem 2000, 43, 1253-1256.): (a) rapid and selective binding of thiol-reactive prodrugs to the cysteine-34 position of endogenous albumin after intravenous administration and (b)...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm020276c

    authors： Kratz F,Warnecke A,Scheuermann K,Stockmar C,Schwab J,Lazar P,Drückes P,Esser N,Drevs J,Rognan D,Bissantz C,Hinderling C,Folkers G,Fichtner I,Unger C

    更新日期：2002-12-05 00:00:00

  • 2-Thiazolylimino/heteroarylimino-5-arylidene-4-thiazolidinones as new agents with SHP-2 inhibitory action.

    abstract：:SHP-2, a nonreceptor protein tyrosine phosphatase encoded by the PTPN11 gene, mediates cell signaling by growth factors and cytokines via the RAS/MAP kinase pathway. Somatic mutations in PTPN11 gene account for approximately 18% of juvenile myelomonocytic leukemia (JMML) patients. Moreover, SHP-2 mutations leading to ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm8004306

    authors： Geronikaki A,Eleftheriou P,Vicini P,Alam I,Dixit A,Saxena AK

    更新日期：2008-09-11 00:00:00

  • Exploring the importance of piperazine N-atoms for sigma(2) receptor affinity and activity in a series of analogs of 1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine (PB28).

    abstract：:sigma(2)-Agonist 1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine (7, PB 28), which proved to revert doxorubicin resistance in breast cancer cells, was taken as a template to prepare new analogs. One of the two basic N-atoms was alternatively replaced by a methine or converted into an a...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm9007505

    authors： Berardi F,Abate C,Ferorelli S,Uricchio V,Colabufo NA,Niso M,Perrone R

    更新日期：2009-12-10 00:00:00

  • Biosensor-based kinetic characterization of the interaction between HIV-1 reverse transcriptase and non-nucleoside inhibitors.

    abstract：:Details of the interaction between HIV-1 reverse transcriptase and non-nucleoside inhibitors (NNRTIs) have been elucidated using a biosensor-based approach. This initial study was performed with HIV-1 reverse transcriptase mutant K103N, the phenethylthioazolylthiourea compound (PETT) MIV-150, and the three NNRTIs lice...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm0504048

    authors： Geitmann M,Unge T,Danielson UH

    更新日期：2006-04-20 00:00:00

  • Modeling of competitive phosphono amino acid NMDA receptor antagonists.

    abstract：:A pharmacophore for the phosphono amino acid antagonists of the NMDA receptor has been developed using computer-based molecular modeling techniques. An important feature of this model is that a single binding site is proposed for the phosphonic acid moiety. All competitive antagonists we have examined incorporating am...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00087a002

    authors： Whitten JP,Harrison BL,Weintraub HJ,McDonald IA

    更新日期：1992-05-01 00:00:00

  • Design, synthesis, and evaluation of N-acyl modified sialic acids as inhibitors of adenoviruses causing epidemic keratoconjunctivitis.

    abstract：:The adenovirus serotype Ad37 binds to and infects human corneal epithelial (HCE) cells through attachment to cellular glycoproteins carrying terminal sialic acids. By use of the crystallographic structure of the sialic acid-interacting domain of the Ad37 fiber protein in complex with sialyllactose, a set of N-acyl mod...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm801609s

    authors： Johansson S,Nilsson E,Qian W,Guilligay D,Crepin T,Cusack S,Arnberg N,Elofsson M

    更新日期：2009-06-25 00:00:00

  • Identifying Medication Targets for Psychostimulant Addiction: Unraveling the Dopamine D3 Receptor Hypothesis.

    abstract：:The dopamine D3 receptor (D3R) is a target for developing medications to treat substance use disorders. D3R-selective compounds with high affinity and varying efficacies have been discovered, providing critical research tools for cell-based studies that have been translated to in vivo models of drug abuse. D3R antagon...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm501512b

    authors： Keck TM,John WS,Czoty PW,Nader MA,Newman AH

    更新日期：2015-07-23 00:00:00

  • Discovery of 4-amino and 4-hydroxy-1-aroylindoles as potent tubulin polymerization inhibitors.

    abstract：:1-Aroylindoline, 1-aroyl-1,2,3,4-tetrahydroquinoline, and 1-aroylindole derivatives were synthesized and evaluated for anticancer activity. The 4-amino and 4-hydroxy-1-aroylindoles 26 and 27 with IC 50 of 0.9 and 0.6 microM, respectively, exhibited antitubulin activity superior or comparable to that of colchicine and ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm800150d

    authors： Liou JP,Wu ZY,Kuo CC,Chang CY,Lu PY,Chen CM,Hsieh HP,Chang JY

    更新日期：2008-07-24 00:00:00

  • Bile Acid Oligomers and Their Combination with Antibiotics To Combat Bacterial Infections.

    abstract：:The ever-growing risk of bacterial resistance is a critical concern. Among the various antimicrobial resistant bacterial strains, methicillin and vancomycin resistant Staphylococcus aureus are among the most dreadful, causing serious complications. On the basis of the hypothesis that microbes have reduced ability to d...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.8b01433

    authors： Singla P,Dalal P,Kaur M,Arya G,Nimesh S,Singh R,Salunke DB

    更新日期：2018-11-21 00:00:00

  • Discovery and structure-activity relationships of sulfonamide ETA-selective antagonists.

    abstract：:Random screening of compounds in an ETA receptor binding assay led to the discovery of a class of benzenesulfonamide ligands. Optimization led to the development of 5-amino-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesulfonamides which were functional antagonists. Structural features which were important to activity in...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00008a013

    authors： Stein PD,Floyd DM,Bisaha S,Dickey J,Girotra RN,Gougoutas JZ,Kozlowski M,Lee VG,Liu EC,Malley MF

    更新日期：1995-04-14 00:00:00

  • Synthesis and radioprotective activity of new cysteamine and cystamine derivatives.

    abstract：:A variety of N-(aminoalkanoyl)-S-acylcysteamine and N,N'-bis(aminoalkanoyl)cystamine salt derivatives were synthesized. Toxicity and radioprotective activity (as the dose reduction factor DRF) were determined in vivo on mice and compared to WR 2721 and S-acetylcysteamine hydrochloride. One of the most interesting comp...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00161a015

    authors： Oiry J,Pue JY,Imbach JL,Fatome M,Sentenac-Roumanou H,Lion C

    更新日期：1986-11-01 00:00:00

  • Development of Benzenesulfonamide Derivatives as Potent Glutathione Transferase Omega-1 Inhibitors.

    abstract：:Glutathione transferase omega-1 (GSTO1-1) is an enzyme whose function supports the activation of interleukin (IL)-1β and IL-18 that are implicated in a variety of inflammatory disease states for which small-molecule inhibitors are sought. The potent reactivity of the active-site cysteine has resulted in reported inhib...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.9b01391

    authors： Xie Y,Tummala P,Oakley AJ,Deora GS,Nakano Y,Rooke M,Cuellar ME,Strasser JM,Dahlin JL,Walters MA,Casarotto MG,Board PG,Baell JB

    更新日期：2020-03-26 00:00:00

  • Corticotropin-releasing hormone receptor antagonists: framework design and synthesis guided by ligand conformational studies.

    abstract：:As described in the preceding paper (Arvanitis et al. J. Med. Chem. 1999, 42), anilinopyrimidines I were identified as potent antagonists of corticotropin-releasing hormone-1 receptor (CRH1-R, also referred to as corticotropin-releasing factor, CRF1-R). Our next goal was to understand the receptor-bound conformation o...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm980223o

    authors： Hodge CN,Aldrich PE,Wasserman ZR,Fernandez CH,Nemeth GA,Arvanitis A,Cheeseman RS,Chorvat RJ,Ciganek E,Christos TE,Gilligan PJ,Krenitsky P,Scholfield E,Strucely P

    更新日期：1999-03-11 00:00:00

  • Structure-activity relationship studies leading to the identification of (2E)-3-[l-[(2,4-dichlorophenyl)methyl]-5-fluoro-3-methyl-lH-indol-7-yl]-N-[(4,5-dichloro-2-thienyl)sulfonyl]-2-propenamide (DG-041), a potent and selective prostanoid EP3 receptor an

    abstract：:The EP(3) receptor on the platelet mediates prostaglandin E(2) potentiation of thrombogenic coagonists including collagen and adenosine diphosphate (ADP). A pharmacophore driven approach led to the identification of diverse peri-substituted heterocycles as potent and selective EP(3) receptor antagonists. A simultaneou...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm9005912

    authors： Singh J,Zeller W,Zhou N,Hategan G,Mishra RK,Polozov A,Yu P,Onua E,Zhang J,Ramírez JL,Sigthorsson G,Thorsteinnsdottir M,Kiselyov AS,Zembower DE,Andrésson T,Gurney ME

    更新日期：2010-01-14 00:00:00

  • Discovery of an Inhibitor of the Proteasome Subunit Rpn11.

    abstract：:The proteasome plays a crucial role in degradation of normal proteins that happen to be constitutively or inducibly unstable, and in this capacity it plays a regulatory role. Additionally, it degrades abnormal/damaged/mutant/misfolded proteins, which serves a quality-control function. Inhibitors of the proteasome have...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.6b01379

    authors： Perez C,Li J,Parlati F,Rouffet M,Ma Y,Mackinnon AL,Chou TF,Deshaies RJ,Cohen SM

    更新日期：2017-02-23 00:00:00

  • Bispyridinium cyclophanes: novel templates for human choline kinase inhibitors.

    abstract：:The synthesis and biological activities of four novel bispyridinium cyclophanes as choline kinase (ChoK) inhibitors are presented. Their synthetic methodology has been optimized according to dilution, temperature, and reaction time and provides pure bispyridinium cyclophanes in high yields very easily. One of these cy...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm030792i

    authors： Conejo-García A,Campos JM,Sánchez-Martín RM,Gallo MA,Espinosa A

    更新日期：2003-08-14 00:00:00

  • Piperazinylquinoxalines with central serotoninmimetic activity.

    abstract：:Regioselective syntheses of substituted 2-chloroquinoxalines and derived 2-(1-piperazinyl)quinoxalines are described. Selectivity in regards to serotonin reuptake blocking and serotoninmimetic activities of the piperazinylquinoxalines is reported. In general, introduction of a 6-substituent into the piperazinylquinoxa...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00133a019

    authors： Lumma WC Jr,Hartman RD,Saari WS,Engelhardt EL,Lotti VJ,Stone CA

    更新日期：1981-01-01 00:00:00

  • Activation of Phenyl 4-(2-Oxo-3-alkylimidazolidin-1-yl)benzenesulfonates Prodrugs by CYP1A1 as New Antimitotics Targeting Breast Cancer Cells.

    abstract：:Prodrug-mediated utilization of the cytochrome P450 (CYP) 1A1 to obtain the selective release of potent anticancer products within cancer tissues is a promising approach in chemotherapy. We herein report the rationale, preparation, biological evaluation, and mechanism of action of phenyl 4-(2-oxo-3-alkylimidazolidin-1...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.7b00343

    authors： Fortin S,Charest-Morin X,Turcotte V,Lauvaux C,Lacroix J,Côté MF,Gobeil S,C-Gaudreault R

    更新日期：2017-06-22 00:00:00

  • Potent and selective fluoroketone inhibitors of group VIA calcium-independent phospholipase A2.

    abstract：:Group VIA calcium-independent phospholipase A(2) (GVIA iPLA(2)) has recently emerged as a novel pharmaceutical target. We have now explored the structure-activity relationship between fluoroketones and GVIA iPLA(2) inhibition. The presence of a naphthyl group proved to be of paramount importance. 1,1,1-Trifluoro-6-(na...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm901872v

    authors： Kokotos G,Hsu YH,Burke JE,Baskakis C,Kokotos CG,Magrioti V,Dennis EA

    更新日期：2010-05-13 00:00:00

  • Synthesis and biological activity of a ketomethylene analogue of a tripeptide inhibitor of angiotensin converting enzyme.

    abstract：:An analogue of a tripeptide inhibitor of angiotensin converting enzyme, Bz-Phe-Gly-Pro, has been synthesized in which the amide bond connecting phenylalanine and glycine has been replaced by a ketomethylene group. This nonpeptide analogue, 20, shows more potent converting enzyme inhibiting activity, I50 = 0.07 microM,...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00186a020

    authors： Almquist RG,Chao WR,Ellis ME,Johnson HL

    更新日期：1980-12-01 00:00:00

  • How are fragments optimized? A retrospective analysis of 145 fragment optimizations.

    abstract：:Fragment optimizations in nearly 150 fragment-based drug discovery programs reported in the literature during the past fifteen years were investigated. By analyzing physicochemical properties and ligand efficiency indices we found that biochemical detection methods yield hits with superior ligand efficiency and lipoph...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm301851v

    authors： Ferenczy GG,Keserű GM

    更新日期：2013-03-28 00:00:00

  • (E)-3-(4-Oxo-4H-quinazolin-3-yl)-2-propenoic acids, a new series of antiallergy agents.

    abstract：:A series of substituted (E)-3-(4-oxo-4H-quinazolin-3-yl)-2-propenoic acids was prepared and evaluated in the rat passive cutaneous anaphylaxis (PCA) test for antiallergic activity. Alkoxy, alkylthio, and isopropyl substituents at the 6- or 8-positions provided highly potent compounds. Conversion to the Z isomer, reduc...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00357a018

    authors： LeMahieu RA,Carson M,Nason WC,Parrish DR,Welton AF,Baruth HW,Yaremko B

    更新日期：1983-03-01 00:00:00

  • Inhibit or Evade Multidrug Resistance P-Glycoprotein in Cancer Treatment.

    abstract：:Multidrug resistance (MDR) is a major cause of failure in cancer chemotherapy. P-glycoprotein (P-gp), a promiscuous drug efflux pump, has been extensively studied for its association with MDR due to overexpression in cancer cells. Several P-gp inhibitors or modulators have been investigated in clinical trials in hope ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章,评审

    doi：10.1021/acs.jmedchem.7b01457

    authors： Waghray D,Zhang Q

    更新日期：2018-06-28 00:00:00

  • Synthesis and antifungal activity of a novel series of alkyldimethylamine cyanoboranes and their derivatives.

    abstract：:A series of new amine cyanoborane derivatives were synthesized and exhibited antifungal activity. A long alkyl chain attached to the nitrogen of the amine cyanoboranes and carboxyboranes enhances antifungal activity. An enhanced activity was also obtained upon the halogenation of the amine cyanoboranes as well as in t...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm060476e

    authors： Takrouri K,Oren G,Polacheck I,Sionov E,Shalom E,Katzhendler J,Srebnik M

    更新日期：2006-08-10 00:00:00

  • Carbocyclic prostaglandin analogs. 1. Steroid carboxylic acids.

    abstract：:Certain structural similarities between prostaglandins with close-packed side chains and the perhydrocyclopentanophenanthrene nucleus of steroids prompted the synthesis and biological evaluation of 6beta, 17 beta-dihydroxy-5alpha-androstane-2alpha-carboxylic acid (30), its 6-deoxy derivative 28, and the corresponding ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00235a002

    authors： Venton DL,Counsell RE,Sanner JH,Sierra K

    更新日期：1975-01-01 00:00:00

  • Novel 1-[2-(diarylmethoxy)ethyl]-2-methyl-5-nitroimidazoles as HIV-1 non-nucleoside reverse transcriptase inhibitors. A structure-activity relationship investigation.

    abstract：:1-[2-(Diarylmethoxy)ethyl]-2-methyl-5-nitroimidazoles (DAMNIs) is a novel family of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) active at submicromolar concentration. Replacement of one phenyl ring of 1-[2-(diphenylmethoxy)ethyl]-2-methyl-5-nitroimidazole (4) with heterocyclic rings, such as 2-thien...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm050273a

    authors： De Martino G,La Regina G,Di Pasquali A,Ragno R,Bergamini A,Ciaprini C,Sinistro A,Maga G,Crespan E,Artico M,Silvestri R

    更新日期：2005-06-30 00:00:00

  • Identification and characterization of small molecule inhibitors of a class I histone deacetylase from Plasmodium falciparum.

    abstract：:A library of approximately 2000 small molecules biased toward inhibition of histone deacetylases was assayed for antimalarial activity in a high-throughput P. falciparum viability assay. Active compounds were cross-analyzed for induction of histone hyperacetylation in a human myeloma cell line to identify HDAC inhibit...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm801654y

    authors： Patel V,Mazitschek R,Coleman B,Nguyen C,Urgaonkar S,Cortese J,Barker RH,Greenberg E,Tang W,Bradner JE,Schreiber SL,Duraisingh MT,Wirth DF,Clardy J

    更新日期：2009-04-23 00:00:00

  • Design of novel, potent, noncovalent inhibitors of thrombin with nonbasic P-1 substructures: rapid structure-activity studies by solid-phase synthesis.

    abstract：:Study of surface representations of the inhibitor-bound thrombin P-1 pocket revealed a lipophilic recess in this pocket which is not occupied by any known inhibitor. Solid-phase synthesis was used to generate benzylamides of D-diphenylAlaPro by aminolysis of Boc dipeptide Kaiser resin. The resulting amides inhibited t...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm9706933

    authors： Lumma WC Jr,Witherup KM,Tucker TJ,Brady SF,Sisko JT,Naylor-Olsen AM,Lewis SD,Lucas BJ,Vacca JP

    更新日期：1998-03-26 00:00:00

  • Synthesis and biological evaluation of analogues of AKT (protein kinase B) inhibitor-IV.

    abstract：:Inhibitors of the PI3-kinase/AKT (protein kinase B) pathway are under investigation as anticancer and antiviral agents. The benzimidazole derivative AKT inhibitor-IV (ChemBridge 5233705) affects this pathway and exhibits potent anticancer and antiviral activity. To probe its biological activity, we synthesized AKT inh...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm100912b

    authors： Sun Q,Wu R,Cai S,Lin Y,Sellers L,Sakamoto K,He B,Peterson BR

    更新日期：2011-03-10 00:00:00