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  1. Article ; Online: Discovery of novel N-acylpyrazoles as potent and selective thrombin inhibitors.

    Short, Kevin M / Estiarte, M Angels / Pham, Son M / Williams, David C / Igoudin, Lev / Dash, Subhadra / Sandoval, Nichole / Datta, Anirban / Pozzi, Nicola / Di Cera, Enrico / Kita, David B

    European journal of medicinal chemistry

    2022  Volume 246, Page(s) 114855

    Abstract: Direct oral anticoagulants (DOACs), which includes thrombin and factor Xa inhibitors, have emerged as the preferred therapeutics for thrombotic disorders, penetrating a market previously dominated by warfarin and heparin. This article describes the ... ...

    Abstract Direct oral anticoagulants (DOACs), which includes thrombin and factor Xa inhibitors, have emerged as the preferred therapeutics for thrombotic disorders, penetrating a market previously dominated by warfarin and heparin. This article describes the discovery and profiling of a novel series of N-acylpyrazoles, which act as selective, covalent, reversible, non-competitive inhibitors of thrombin. We describe in vitro stability issues associated with this chemotype and, importantly, demonstrate that N-acylpyrazoles successfully act in vivo as anticoagulants in basic thrombotic animal models. Crucially, this anticoagulant nature is unaccompanied by the higher bleeding risk profile that has become an undesirable characteristic of the DTIs and factor Xa inhibitors. We propose that the N-acylpyrazole chemotype shows intriguing promise as next-generation oral anticoagulants.
    Language English
    Publishing date 2022-10-27
    Publishing country France
    Document type Journal Article
    ZDB-ID 188597-2
    ISSN 1768-3254 ; 0009-4374 ; 0223-5234
    ISSN (online) 1768-3254
    ISSN 0009-4374 ; 0223-5234
    DOI 10.1016/j.ejmech.2022.114855
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: VE-1902-A direct thrombin inhibitor with reversible covalent mechanism of action shows efficacy with reduced bleeding in rodent models of thrombosis.

    Sivaraja, Mohanram / Clemens, Daniel M / Sizikov, Sivan / Dash, Subhadra / Xu, Chengpei / Rienzo, Matthew / Yang, Bo / Ryan, Molly / Chattopadhyay, Madhuri / Igoudin, Lev / Chang, Stephanie S / Keutzer, Samuel / Zalicki, Piotr / Estiarte, M Angels / Shiau, Timothy P / Short, Kevin M / Williams, David C / Datta, Anirban / Pozzi, Nicola /
    Di Cera, Enrico / Gibson, C Michael / Fox, Keith A A / Kita, David B

    Thrombosis research

    2020  Volume 190, Page(s) 112–121

    Abstract: Introduction: High incidence of bleeding events remains a key risk for patients taking anticoagulants, especially those in need of long-term combination therapy with antiplatelet agents. As a consequence, patients may not receive clinically indicated ... ...

    Abstract Introduction: High incidence of bleeding events remains a key risk for patients taking anticoagulants, especially those in need of long-term combination therapy with antiplatelet agents. As a consequence, patients may not receive clinically indicated combination antithrombotic therapy. Here, we report on VE-1902, a member of a novel class of precision oral anticoagulants (PROACs) that combines effective anticoagulation with reduced bleeding in preclinical testing.
    Methods and results: Acting through covalent, reversible active-site modification of thrombin similar to a previously described molecule [1], VE-1902 shows potency and selectivity for thrombin inhibition in human plasma comparable to clinically relevant direct thrombin inhibitors (DTI) such as argatroban and dabigatran (thrombin generation assay ETP EC
    Conclusions: By leaving platelet activation following vascular injury mostly unaffected, VE-1902, and the PROACs more generally, represent a new generation of precision anticoagulants with reduced bleeding risk.
    MeSH term(s) Animals ; Anticoagulants/pharmacology ; Anticoagulants/therapeutic use ; Antithrombins ; Hemorrhage/chemically induced ; Hemorrhage/drug therapy ; Humans ; Rodentia ; Thrombin ; Thrombosis/drug therapy
    Chemical Substances Anticoagulants ; Antithrombins ; Thrombin (EC 3.4.21.5)
    Language English
    Publishing date 2020-04-19
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 121852-9
    ISSN 1879-2472 ; 0049-3848
    ISSN (online) 1879-2472
    ISSN 0049-3848
    DOI 10.1016/j.thromres.2020.04.020
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  3. Article ; Online: Reversible covalent direct thrombin inhibitors.

    Sivaraja, Mohanram / Pozzi, Nicola / Rienzo, Matthew / Lin, Kenneth / Shiau, Timothy P / Clemens, Daniel M / Igoudin, Lev / Zalicki, Piotr / Chang, Stephanie S / Estiarte, M Angels / Short, Kevin M / Williams, David C / Datta, Anirban / Di Cera, Enrico / Kita, David B

    PloS one

    2018  Volume 13, Issue 8, Page(s) e0201377

    Abstract: Introduction: In recent years, the traditional treatments for thrombotic diseases, heparin and warfarin, are increasingly being replaced by novel oral anticoagulants offering convenient dosing regimens, more predictable anticoagulant responses, and less ...

    Abstract Introduction: In recent years, the traditional treatments for thrombotic diseases, heparin and warfarin, are increasingly being replaced by novel oral anticoagulants offering convenient dosing regimens, more predictable anticoagulant responses, and less frequent monitoring. However, these drugs can be contraindicated for some patients and, in particular, their bleeding liability remains high.
    Methods: We have developed a new class of direct thrombin inhibitors (VE-DTIs) and have utilized kinetics, biochemical, and X-ray structural studies to characterize the mechanism of action and in vitro pharmacology of an exemplary compound from this class, Compound 1.
    Results: We demonstrate that Compound 1, an exemplary VE-DTI, acts through reversible covalent inhibition. Compound 1 inhibits thrombin by transiently acylating the active site S195 with high potency and significant selectivity over other trypsin-like serine proteases. The compound inhibits the binding of a peptide substrate with both clot-bound and free thrombin with nanomolar potency. Compound 1 is a low micromolar inhibitor of thrombin activity against endogenous substrates such as fibrinogen and a nanomolar inhibitor of the activation of protein C and thrombin-activatable fibrinolysis inhibitor. In the thrombin generation assay, Compound 1 inhibits thrombin generation with low micromolar potency but does not increase the lag time for thrombin formation. In addition, Compound 1 showed weak inhibition of clotting in PT and aPTT assays consistent with its distinctive profile in the thrombin generation assay.
    Conclusion: Compound 1, while maintaining strong potency comparable to the current DTIs, has a distinct mechanism of action which produces a differentiating pharmacological profile. Acting through reversible covalent inhibition, these direct thrombin inhibitors could lead to new anticoagulants with better combined efficacy and bleeding profiles.
    MeSH term(s) Antithrombins/chemistry ; Catalytic Domain ; Crystallography, X-Ray ; Humans ; Models, Chemical ; Thrombin/chemistry
    Chemical Substances Antithrombins ; Thrombin (EC 3.4.21.5)
    Language English
    Publishing date 2018-08-02
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0201377
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  4. Article: Discovery of ADDL--targeting small molecule drugs for Alzheimer's disease.

    Look, Gary C / Jerecic, Jasna / Cherbavaz, Diana B / Pray, Todd R / Breach, Jean-Claude R / Crosier, Walter J / Igoudin, Lev / Hironaka, Catherine M / Lowe, Raymond M / McEntee, Michele / Ruslim-Litrus, Lily / Wu, Hsiu-Mei / Zhang, Sue / Catalano, Susan M / Goure, William F / Summa, David / Krafft, Grant A

    Current Alzheimer research

    2007  Volume 4, Issue 5, Page(s) 562–567

    Abstract: Amyloid beta-derived diffusible ligands (ADDLs) comprise the neurotoxic subset of soluble Abeta(1-42) oligomers, now widely considered to be the molecular cause of memory malfunction and neurodegeneration in Alzheimer's disease (AD). We have developed a ... ...

    Abstract Amyloid beta-derived diffusible ligands (ADDLs) comprise the neurotoxic subset of soluble Abeta(1-42) oligomers, now widely considered to be the molecular cause of memory malfunction and neurodegeneration in Alzheimer's disease (AD). We have developed a screening cascade which identifies small molecule modulators of ADDL-mediated neurotoxicity. The primary screen involves a fluorescence resonance energy transfer (FRET)-based assay which selects inhibitors of Abeta1-42 oligomer assembly. The identified hits were further characterized by assessing their ability to inhibit the assembly and binding of ADDLs to cultures of primary hippocampal neurons. This approach has led to the identification of a number of small molecules which inhibit ADDL assembly and their subsequent binding to neurons. Here we describe our small molecule discovery efforts to identify ADDL assembly blocker and ADDL binding inhibitors, and to transform validated hits into pre-clinical lead compounds.
    MeSH term(s) Alzheimer Disease/drug therapy ; Amyloid beta-Peptides/antagonists & inhibitors ; Amyloid beta-Peptides/chemistry ; Amyloid beta-Peptides/metabolism ; Animals ; Antipsychotic Agents/chemistry ; Antipsychotic Agents/therapeutic use ; Drug Design ; Humans ; Small Molecule Libraries
    Chemical Substances Amyloid beta-Peptides ; Antipsychotic Agents ; Small Molecule Libraries
    Language English
    Publishing date 2007-12-20
    Publishing country United Arab Emirates
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2205170-3
    ISSN 1567-2050
    ISSN 1567-2050
    DOI 10.2174/156720507783018271
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 6235: Show issues Location:
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