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  1. Article: Discovery of Novel NLRP3 Inflammasome Inhibitors Composed of an Oxazole Scaffold Bearing an Acylsulfamide.

    Ohba, Yusuke / Adachi, Kaoru / Furukawa, Takayuki / Nishimaru, Tatsuya / Sakurai, Kentaro / Masuo, Ritsuki / Inami, Tasuku / Orita, Takuya / Akai, Shota / Adachi, Tsuyoshi / Usui, Kenji / Hamada, Yuji / Mori, Mutsuki / Kurimoto, Takafumi / Wakashima, Takeshi / Akiyama, Yoshiyuki / Miyazaki, Susumu / Noji, Satoru

    ACS medicinal chemistry letters

    2023  Volume 14, Issue 12, Page(s) 1833–1838

    Abstract: The NLRP3 inflammasome plays an important role in the defense mechanism of the innate immune system and has recently attracted much attention as a drug target for various inflammatory disorders. Among the strategies for generating the novel chemotype in ... ...

    Abstract The NLRP3 inflammasome plays an important role in the defense mechanism of the innate immune system and has recently attracted much attention as a drug target for various inflammatory disorders. Among the strategies for generating the novel chemotype in current drug discovery, scaffold hopping and bioisosteric replacement are known to be attractive approaches. As the results of our medicinal chemistry campaign, which involved exploration of core motifs using a ring closing approach, a five-membered oxazole-based scaffold was identified, and subsequent implementation of bioisosteric replacement led to discovery of a novel chemical class of NLRP3 inflammasome inhibitor bearing the acylsulfamide group. Further optimization of aniline and sulfamide moieties to improve potency in human whole blood assay led to the identification of the orally bioactive compound
    Language English
    Publishing date 2023-11-10
    Publishing country United States
    Document type Journal Article
    ISSN 1948-5875
    ISSN 1948-5875
    DOI 10.1021/acsmedchemlett.3c00433
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: The crystal structure of homoserine dehydrogenase complexed with l-homoserine and NADPH in a closed form.

    Akai, Shota / Ikushiro, Hiroko / Sawai, Taiki / Yano, Takato / Kamiya, Nobuo / Miyahara, Ikuko

    Journal of biochemistry

    2018  Volume 165, Issue 2, Page(s) 185–195

    Abstract: Homoserine dehydrogenase from Thermus thermophilus (TtHSD) is a key enzyme in the aspartate pathway that catalyses the reversible conversion of l-aspartate-β-semialdehyde to l-homoserine (l-Hse) with NAD(P)H. We determined the crystal structures of ... ...

    Abstract Homoserine dehydrogenase from Thermus thermophilus (TtHSD) is a key enzyme in the aspartate pathway that catalyses the reversible conversion of l-aspartate-β-semialdehyde to l-homoserine (l-Hse) with NAD(P)H. We determined the crystal structures of unliganded TtHSD, TtHSD complexed with l-Hse and NADPH, and Lys99Ala and Lys195Ala mutant TtHSDs, which have no enzymatic activity, complexed with l-Hse and NADP+ at 1.83, 2.00, 1.87 and 1.93 Å resolutions, respectively. Binding of l-Hse and NADPH induced the conformational changes of TtHSD from an open to a closed form: the mobile loop containing Glu180 approached to fix l-Hse and NADPH, and both Lys99 and Lys195 could make hydrogen bonds with the hydroxy group of l-Hse. The ternary complex of TtHSDs in the closed form mimicked a Michaelis complex better than the previously reported open form structures from other species. In the crystal structure of Lys99Ala TtHSD, the productive geometry of the ternary complex was almost preserved with one new water molecule taking over the hydrogen bonds associated with Lys99, while the positions of Lys195 and l-Hse were significantly retained with those of the wild-type enzyme. These results propose new possibilities that Lys99 is the acid-base catalytic residue of HSDs.
    MeSH term(s) Crystallography, X-Ray ; Homoserine/chemistry ; Homoserine/metabolism ; Homoserine Dehydrogenase/chemistry ; Homoserine Dehydrogenase/metabolism ; Models, Molecular ; NADP/chemistry ; NADP/metabolism ; Protein Conformation ; Thermus thermophilus/enzymology
    Chemical Substances NADP (53-59-8) ; Homoserine (6KA95X0IVO) ; Homoserine Dehydrogenase (EC 1.1.1.3)
    Language English
    Publishing date 2018-11-13
    Publishing country England
    Document type Journal Article
    ZDB-ID 218073-x
    ISSN 1756-2651 ; 0021-924X
    ISSN (online) 1756-2651
    ISSN 0021-924X
    DOI 10.1093/jb/mvy094
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. 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

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    Zs.B 151: Show issues Location:
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