LIVIVO - The Search Portal for Life Sciences

zur deutschen Oberfläche wechseln
Advanced search

Search results

Result 1 - 7 of total 7

Search options

  1. Article ; Online: Discovery and SAR of JTE-151: A Novel RORγ Inhibitor for Clinical Development.

    Maeba, Takaki / Hirata, Kazuyuki / Kotoku, Masayuki / Seki, Noriyoshi / Maeda, Katsuya / Hirashima, Shintaro / Yamanaka, Hiroshi / Sakai, Takayuki / Obika, Shingo / Hori, Akimi / Hara, Yoshinori / Noji, Satoru / Suwa, Yoshihiro / Yokota, Masahiro / Fujioka, Shingo / Yamaguchi, Takayuki / Katsuda, Yoshiaki / Hata, Takahiro / Miyagawa, Naoki /
    Arita, Kojo / Nomura, Yukihiro / Taniguchi, Toshio / Asahina, Kota / Aratsu, Yusuke / Naka, Yuichi / Adachi, Tsuyoshi / Nomura, Akihiro / Akai, Shota / Oshida, Shin-Ichi / Pai, Sudhakar / Crowe, Paul / Bradley, Erin / Steensma, Ruo / Tao, Haiyan / Fenn, Morgan / Babine, Robert / Li, Xiaolin / Thacher, Scott / Soeta, Takahiro / Ukaji, Yutaka / Shiozaki, Makoto

    Journal of medicinal chemistry

    2024  Volume 67, Issue 2, Page(s) 952–970

    Abstract: A number of RORγ inhibitors have been reported over the past decade. There were also several examples advancing to human clinical trials, however, none of them has reached the market yet, suggesting that there could be common obstacles for their future ... ...

    Abstract A number of RORγ inhibitors have been reported over the past decade. There were also several examples advancing to human clinical trials, however, none of them has reached the market yet, suggesting that there could be common obstacles for their future development. As was expected from the general homology of nuclear receptor ligands, insufficient selectivity as well as poor physicochemical properties were identified as potential risks for a RORγ program. Based on such considerations, we conducted a SAR investigation by prioritizing drug-like properties to mitigate such potential drawbacks. After an intensive SAR exploration with strong emphasis on "drug-likeness" indices, an orally available RORγ inhibitor, JTE-151, was finally generated and was advanced to a human clinical trial. The compound was confirmed to possess highly selective profiles along with good metabolic stability, and most beneficially, no serious adverse events (SAE) and good PK profiles were observed in the human clinical trial.
    Language English
    Publishing date 2024-01-03
    Publishing country United States
    Document type Journal Article
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/acs.jmedchem.3c01933
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    In stock of ZB MED Cologne/Königswinter

    Zs.B 151: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)
    Zs.MB 1: Show issues

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  2. Article ; Online: Ternary crystal structure of human RORγ ligand-binding-domain, an inhibitor and corepressor peptide provides a new insight into corepressor interaction.

    Noguchi, Masato / Nomura, Akihiro / Doi, Satoki / Yamaguchi, Keishi / Hirata, Kazuyuki / Shiozaki, Makoto / Maeda, Katsuya / Hirashima, Shintaro / Kotoku, Masayuki / Yamaguchi, Takayuki / Katsuda, Yoshiaki / Crowe, Paul / Tao, Haiyan / Thacher, Scott / Adachi, Tsuyoshi

    Scientific reports

    2018  Volume 8, Issue 1, Page(s) 17374

    Abstract: Retinoic acid-related orphan receptor gamma (RORγ) plays pivotal roles in autoimmune diseases by controlling the lineage of interleukin 17 (IL-17)-producing ... ...

    Abstract Retinoic acid-related orphan receptor gamma (RORγ) plays pivotal roles in autoimmune diseases by controlling the lineage of interleukin 17 (IL-17)-producing CD4
    MeSH term(s) Autoimmune Diseases/metabolism ; Co-Repressor Proteins/metabolism ; Humans ; Interleukin-17/metabolism ; Nuclear Receptor Subfamily 1, Group F, Member 3/chemistry ; Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism ; Peptides/metabolism ; Protein Binding ; Protein Domains/physiology ; Structure-Activity Relationship ; Th17 Cells/metabolism
    Chemical Substances Co-Repressor Proteins ; Interleukin-17 ; Nuclear Receptor Subfamily 1, Group F, Member 3 ; Peptides
    Language English
    Publishing date 2018-11-26
    Publishing country England
    Document type Journal Article
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-018-35783-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  3. Article ; Online: Discovery of Second Generation RORγ Inhibitors Composed of an Azole Scaffold.

    Kotoku, Masayuki / Maeba, Takaki / Fujioka, Shingo / Yokota, Masahiro / Seki, Noriyoshi / Ito, Keisuke / Suwa, Yoshihiro / Ikenogami, Taku / Hirata, Kazuyuki / Hase, Yasunori / Katsuda, Yoshiaki / Miyagawa, Naoki / Arita, Kojo / Asahina, Kota / Noguchi, Masato / Nomura, Akihiro / Doi, Satoki / Adachi, Tsuyoshi / Crowe, Paul /
    Tao, Haiyan / Thacher, Scott / Hashimoto, Hiromasa / Suzuki, Takayoshi / Shiozaki, Makoto

    Journal of medicinal chemistry

    2019  Volume 62, Issue 5, Page(s) 2837–2842

    Abstract: Starting from a previously reported RORγ inhibitor (1), successive efforts to improve in vivo potency were continued. Introduction of metabolically beneficial motifs in conjunction with scaffold hopping was examined, resulting in discovery of the second ... ...

    Abstract Starting from a previously reported RORγ inhibitor (1), successive efforts to improve in vivo potency were continued. Introduction of metabolically beneficial motifs in conjunction with scaffold hopping was examined, resulting in discovery of the second generation RORγ inhibitor composed of a 4-(isoxazol-3-yl)butanoic acid scaffold (24). Compound 24 achieved a 10-fold improvement in in vivo potency in a mouse CD3 challenge model along with significant anti-inflammatory effects in a mouse dermatitis model.
    MeSH term(s) Animals ; Azoles/chemistry ; Azoles/pharmacology ; Dermatitis/drug therapy ; Disease Models, Animal ; Drug Discovery ; Mice ; Molecular Docking Simulation ; Nuclear Receptor Subfamily 1, Group F, Member 3/antagonists & inhibitors ; Structure-Activity Relationship
    Chemical Substances Azoles ; Nuclear Receptor Subfamily 1, Group F, Member 3
    Language English
    Publishing date 2019-03-01
    Publishing country United States
    Document type Journal Article
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/acs.jmedchem.8b01567
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    In stock of ZB MED Cologne/Königswinter

    Zs.B 151: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)
    Zs.MB 1: Show issues

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  4. Article ; Online: Ternary complex of human RORγ ligand-binding domain, inverse agonist and SMRT peptide shows a unique mechanism of corepressor recruitment.

    Noguchi, Masato / Nomura, Akihiro / Murase, Ken / Doi, Satoki / Yamaguchi, Keishi / Hirata, Kazuyuki / Shiozaki, Makoto / Hirashima, Shintaro / Kotoku, Masayuki / Yamaguchi, Takayuki / Katsuda, Yoshiaki / Steensma, Ruo / Li, Xioalin / Tao, Haiyan / Tse, Bruno / Fenn, Morgan / Babine, Robert / Bradley, Erin / Crowe, Paul /
    Thacher, Scott / Adachi, Tsuyoshi / Kamada, Masafumi

    Genes to cells : devoted to molecular & cellular mechanisms

    2017  Volume 22, Issue 6, Page(s) 535–551

    Abstract: Retinoid-related orphan receptor gamma (RORγ) directly controls the differentiation of Th17 cell and the production of interleukin-17, which plays an integral role in autoimmune diseases. To obtain insight into RORγ, we have determined the first crystal ... ...

    Abstract Retinoid-related orphan receptor gamma (RORγ) directly controls the differentiation of Th17 cell and the production of interleukin-17, which plays an integral role in autoimmune diseases. To obtain insight into RORγ, we have determined the first crystal structure of a ternary complex containing RORγ ligand-binding domain (LBD) bound with a novel synthetic inhibitor and a repressor peptide, 22-mer peptide from silencing mediator of retinoic acid and thyroid hormone receptor (SMRT). Comparison of a binary complex of nonliganded (apo) RORγ-LBD with a nuclear receptor co-activator (NCoA-1) peptide has shown that our inhibitor displays a unique mechanism different from those caused by natural inhibitor, ursolic acid (UA). The compound unprecedentedly induces indirect disruption of a hydrogen bond between His479 on helix 11 (H11) and Tyr502 on H12, which is crucial for active conformation. This crystallographic study will allow us to develop novel synthetic compounds for autoimmune disease therapy.
    MeSH term(s) Binding Sites ; Humans ; Hydrogen Bonding ; Models, Molecular ; Mutation ; Nuclear Receptor Co-Repressor 2/agonists ; Nuclear Receptor Co-Repressor 2/chemistry ; Nuclear Receptor Co-Repressor 2/genetics ; Nuclear Receptor Co-Repressor 2/metabolism ; Nuclear Receptor Coactivator 1/chemistry ; Nuclear Receptor Coactivator 1/genetics ; Nuclear Receptor Coactivator 1/metabolism ; Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism ; Peptide Fragments ; Protein Binding ; Protein Conformation ; Triterpenes/pharmacology ; Ursolic Acid
    Chemical Substances NCOR2 protein, human ; Nuclear Receptor Co-Repressor 2 ; Nuclear Receptor Subfamily 1, Group F, Member 3 ; Peptide Fragments ; Triterpenes ; NCOA1 protein, human (EC 2.3.1.48) ; Nuclear Receptor Coactivator 1 (EC 2.3.1.48)
    Language English
    Publishing date 2017-05-11
    Publishing country England
    Document type Journal Article
    ZDB-ID 1330000-3
    ISSN 1365-2443 ; 1356-9597
    ISSN (online) 1365-2443
    ISSN 1356-9597
    DOI 10.1111/gtc.12494
    Database MEDical Literature Analysis and Retrieval System OnLINE

    Full text online

    More links

    Kategorien

    In stock of ZB MED Cologne/Königswinter

    Zs.A 4539: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  5. Article ; Online: Potent, selective and cell penetrant inhibitors of SF-1 by functional ultra-high-throughput screening.

    Madoux, Franck / Li, Xiaolin / Chase, Peter / Zastrow, Gina / Cameron, Michael D / Conkright, Juliana J / Griffin, Patrick R / Thacher, Scott / Hodder, Peter

    Molecular pharmacology

    2008  Volume 73, Issue 6, Page(s) 1776–1784

    Abstract: The steroidogenic factor 1 (SF-1, also known as NR5A1) is a transcription factor belonging to the nuclear receptor superfamily. Whereas most of the members of this family have been extensively characterized, the therapeutic potential and pharmacology of ... ...

    Abstract The steroidogenic factor 1 (SF-1, also known as NR5A1) is a transcription factor belonging to the nuclear receptor superfamily. Whereas most of the members of this family have been extensively characterized, the therapeutic potential and pharmacology of SF-1 still remains elusive. Described here is the identification and characterization of selective inhibitory chemical probes of SF-1 by a rational ultra-high-throughput screening (uHTS) strategy. A set of 64,908 compounds from the National Institute of Health's Molecular Libraries Small Molecule Repository was screened in a transactivation cell-based assay employing a chimeric SF-1 construct. Two analogous isoquinolinones, ethyl 2-[2-[2-(2,3-dihydro-1,4-benzodioxin-7-ylamino)-2-oxoethyl]-1-oxoisoquinolin-5-yl]oxypropanoate (SID7969543) and ethyl 2-[2-[2-(1,3-benzodioxol-5-ylmethylamino)-2-oxoethyl]-1-oxoisoquinolin-5-yl]oxypropanoate and (SID7970631), were identified as potent submicromolar inhibitors, yielding IC(50) values of 760 and 260 nM. The compounds retained their potency in a more physiologic functional assay employing the full-length SF-1 protein and its native response element, yielding IC(50) values of 30 and 16 nM, respectively. The selectivity of these isoquinolinones was confirmed via transactivation-based functional assays for RAR-related orphan receptor A (RORA), Herpes simplex virus transcriptional activator protein Vmw65 (VP16), and liver receptor homolog 1 (LRH-1). Their cytotoxicity, solubility, permeability and metabolic stability were also measured. These isoquinolinones represent valuable chemical probes to investigate the therapeutic potential of SF-1.
    MeSH term(s) Animals ; CHO Cells ; Cricetinae ; Cricetulus ; Dogs ; Haplorhini ; Humans ; Isoquinolines/chemistry ; Isoquinolines/pharmacology ; Mice ; Rats ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/pharmacology ; Steroidogenic Factor 1/antagonists & inhibitors ; Steroidogenic Factor 1/metabolism
    Chemical Substances Isoquinolines ; Small Molecule Libraries ; Steroidogenic Factor 1
    Language English
    Publishing date 2008-03-11
    Publishing country United States
    Document type Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 124034-1
    ISSN 1521-0111 ; 0026-895X
    ISSN (online) 1521-0111
    ISSN 0026-895X
    DOI 10.1124/mol.108.045963
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    In stock of ZB MED Cologne/Königswinter

    Zs.A 525: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  6. Article: Dealing with experts: the recombinant DNA debate.

    Park, Bob / Thacher, Scott

    Science for the people

    1977  Volume 9, Issue 5, Page(s) 28–35

    MeSH term(s) Community Participation ; DNA, Recombinant ; Federal Government ; Government ; Government Regulation ; Humans ; Industry ; Legislation as Topic ; Local Government ; Public Policy ; Risk ; Risk Assessment ; Social Control, Formal ; Universities
    Chemical Substances DNA, Recombinant
    Language English
    Publishing date 1977-09
    Publishing country United States
    Document type Journal Article
    ISSN 0048-9662
    ISSN 0048-9662
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

    Inter-library loan at ZB MED

    Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

  7. Article: SAR Exploration Guided by LE and Fsp(3): Discovery of a Selective and Orally Efficacious RORγ Inhibitor.

    Hirata, Kazuyuki / Kotoku, Masayuki / Seki, Noriyoshi / Maeba, Takaki / Maeda, Katsuya / Hirashima, Shintaro / Sakai, Takayuki / Obika, Shingo / Hori, Akimi / Hase, Yasunori / Yamaguchi, Takayuki / Katsuda, Yoshiaki / Hata, Takahiro / Miyagawa, Naoki / Arita, Kojo / Nomura, Yukihiro / Asahina, Kota / Aratsu, Yusuke / Kamada, Masafumi /
    Adachi, Tsuyoshi / Noguchi, Masato / Doi, Satoki / Crowe, Paul / Bradley, Erin / Steensma, Ruo / Tao, Haiyan / Fenn, Morgan / Babine, Robert / Li, Xiaolin / Thacher, Scott / Hashimoto, Hiromasa / Shiozaki, Makoto

    ACS medicinal chemistry letters

    2015  Volume 7, Issue 1, Page(s) 23–27

    Abstract: A novel series of RORγ inhibitors was identified starting with the HTS hit 1. After SAR investigation based on a prospective consideration of two drug-likeness metrics, ligand efficiency (LE) and fraction of sp(3) carbon atoms (Fsp(3)), significant ... ...

    Abstract A novel series of RORγ inhibitors was identified starting with the HTS hit 1. After SAR investigation based on a prospective consideration of two drug-likeness metrics, ligand efficiency (LE) and fraction of sp(3) carbon atoms (Fsp(3)), significant improvement of metabolic stability as well as reduction of CYP inhibition was observed, which finally led to discovery of a selective and orally efficacious RORγ inhibitor 3z.
    Language English
    Publishing date 2015-11-04
    Publishing country United States
    Document type Journal Article
    ISSN 1948-5875
    ISSN 1948-5875
    DOI 10.1021/acsmedchemlett.5b00253
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

    Inter-library loan at ZB MED

    Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

To top