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  1. Article ; Online: Nitriles: an attractive approach to the development of covalent inhibitors.

    Bonatto, Vinícius / Lameiro, Rafael F / Rocho, Fernanda R / Lameira, Jerônimo / Leitão, Andrei / Montanari, Carlos A

    RSC medicinal chemistry

    2022  Volume 14, Issue 2, Page(s) 201–217

    Abstract: Nitriles have broad applications in medicinal chemistry, with more than 60 small molecule drugs on the market containing the cyano functional group. In addition to the well-known noncovalent interactions that nitriles can perform with macromolecular ... ...

    Abstract Nitriles have broad applications in medicinal chemistry, with more than 60 small molecule drugs on the market containing the cyano functional group. In addition to the well-known noncovalent interactions that nitriles can perform with macromolecular targets, they are also known to improve drug candidates' pharmacokinetic profiles. Moreover, the cyano group can be used as an electrophilic warhead to covalently bind an inhibitor to a target of interest, forming a covalent adduct, a strategy that can present benefits over noncovalent inhibitors. This approach has gained much notoriety in recent years, mainly with diabetes and COVID-19-approved drugs. Nevertheless, the application of nitriles in covalent ligands is not restricted to it being the reactive center, as it can also be employed to convert irreversible inhibitors into reversible ones, a promising strategy for kinase inhibition and protein degradation. In this review, we introduce and discuss the roles of the cyano group in covalent inhibitors, how to tune its reactivity and the possibility of achieving selectivity only by replacing the warhead. Finally, we provide an overview of nitrile-based covalent compounds in approved drugs and inhibitors recently described in the literature.
    Language English
    Publishing date 2022-11-07
    Publishing country England
    Document type Journal Article ; Review
    ISSN 2632-8682
    ISSN (online) 2632-8682
    DOI 10.1039/d2md00204c
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: A patent review on cathepsin K inhibitors to treat osteoporosis (2011 - 2021).

    Rocho, Fernanda R / Bonatto, Vinícius / Lameiro, Rafael F / Lameira, Jerônimo / Leitão, Andrei / Montanari, Carlos A

    Expert opinion on therapeutic patents

    2022  Volume 32, Issue 5, Page(s) 561–573

    Abstract: Introduction: Cathepsin K (CatK) is a lysosomal cysteine protease and the predominant cathepsin expressed in osteoclasts, where it degrades the bone matrix. Hence, CatK is an attractive therapeutic target related to diseases characterized by bone ... ...

    Abstract Introduction: Cathepsin K (CatK) is a lysosomal cysteine protease and the predominant cathepsin expressed in osteoclasts, where it degrades the bone matrix. Hence, CatK is an attractive therapeutic target related to diseases characterized by bone resorption, like osteoporosis.
    Areas covered: This review summarizes the patent literature from 2011 to 2021 on CatK inhibitors and their potential use as new treatments for osteoporosis. The inhibitors were classified by their warheads, with the most explored nitrile-based inhibitors. Promising in vivo results have also been disclosed.
    Expert opinion: As one of the most potent lysosomal proteins whose primary function is to mediate bone resorption, cathepsin K remains an excellent target for therapeutic intervention. Nevertheless, there is no record of any approved drug that targets CatK. The most notable cases of drug candidates targeting CatK were balicatib and odanacatib, which reached Phase II and III clinical trials, respectively, but did not enter the market. Further developments include exploring new chemical entities beyond the nitrile-based chemical space, with improved ADME and safety profiles. In addition, CatK's role in cancer immunoexpression and its involvement in the pathophysiology of osteo- and rheumatoid arthritis have raised the race to develop activity-based probes with excellent potency and selectivity.
    MeSH term(s) Bone Resorption/drug therapy ; Cathepsin K/metabolism ; Humans ; Nitriles/pharmacology ; Nitriles/therapeutic use ; Osteoporosis/drug therapy ; Patents as Topic
    Chemical Substances Nitriles ; Cathepsin K (EC 3.4.22.38)
    Language English
    Publishing date 2022-03-10
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 1186201-4
    ISSN 1744-7674 ; 0962-2594 ; 1354-3776
    ISSN (online) 1744-7674
    ISSN 0962-2594 ; 1354-3776
    DOI 10.1080/13543776.2022.2040480
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 3962: Show issues Location:
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    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
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  3. Article ; Online: Differential specificity of SARS-CoV-2 main protease variants on peptide versus protein-based substrates.

    Rocho, Fernanda R / Snipas, Scott J / Shamim, Anwar / Rut, Wioletta / Drag, Marcin / Montanari, Carlos A / Salvesen, Guy S

    The FEBS journal

    2023  Volume 291, Issue 1, Page(s) 61–69

    Abstract: The SARS-CoV-2 main protease ( ... ...

    Abstract The SARS-CoV-2 main protease (M
    MeSH term(s) Humans ; SARS-CoV-2/genetics ; COVID-19/genetics ; Viral Nonstructural Proteins/genetics ; Peptides/genetics ; Coronavirus 3C Proteases/genetics ; Protease Inhibitors/chemistry ; Antiviral Agents/pharmacology ; Peptide Hydrolases
    Chemical Substances 3C-like proteinase, SARS-CoV-2 (EC 3.4.22.-) ; Viral Nonstructural Proteins ; Peptides ; Coronavirus 3C Proteases (EC 3.4.22.28) ; Protease Inhibitors ; Antiviral Agents ; Peptide Hydrolases (EC 3.4.-)
    Language English
    Publishing date 2023-11-03
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2173655-8
    ISSN 1742-4658 ; 1742-464X
    ISSN (online) 1742-4658
    ISSN 1742-464X
    DOI 10.1111/febs.16970
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 260: Show issues Location:
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    Jg. 1995 - 2021: Lesesall (1.OG)
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  4. Article ; Online: Nitrile-based peptoids as cysteine protease inhibitors.

    Alves, Luana / Santos, Deborah A / Cendron, Rodrigo / Rocho, Fernanda R / Matos, Thiago K B / Leitão, Andrei / Montanari, Carlos A

    Bioorganic & medicinal chemistry

    2021  Volume 41, Page(s) 116211

    Abstract: Peptidomimetics of the class of dipeptidyl nitrile analog peptoids were synthesized as inhibitors of mammalian cysteine proteases of the papain superfamily. The dipeptidyl nitrile side chains were attached to the peptide backbone's nitrogen atom, not to ... ...

    Abstract Peptidomimetics of the class of dipeptidyl nitrile analog peptoids were synthesized as inhibitors of mammalian cysteine proteases of the papain superfamily. The dipeptidyl nitrile side chains were attached to the peptide backbone's nitrogen atom, not to the α-carbons. Synthesized nitrile-based peptoid analogs that lack the hydrogen amide at P2-P3 are responsible for many of the secondary structure elements in peptides and proteins, making them resistant to proteolysis. The designed peptoids would lose a hydrogen bond with cruzain Asp161 decreasing the affinity toward the enzyme. A structure-activity relationship and matched molecular pair-based analysis between the dipeptidyl nitrile Neq0409 and its peptoid 4a yielded the following cruzain affinities: pK
    MeSH term(s) Cysteine Proteinase Inhibitors/chemistry ; Cysteine Proteinase Inhibitors/pharmacology ; Models, Molecular ; Molecular Docking Simulation ; Molecular Structure ; Nitriles/chemistry ; Peptides/chemistry ; Peptides/pharmacology
    Chemical Substances Cysteine Proteinase Inhibitors ; Nitriles ; Peptides
    Language English
    Publishing date 2021-05-10
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1161284-8
    ISSN 1464-3391 ; 0968-0896
    ISSN (online) 1464-3391
    ISSN 0968-0896
    DOI 10.1016/j.bmc.2021.116211
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 3815: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
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    ab Jg. 2022: Lesesaal (EG)

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