دورية أكاديمية
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Discovery of a Novel Series of Potent, Selective, Orally Available, and Brain-Penetrable C1s Inhibitors for Modulation of the Complement Pathway.

التفاصيل البيبلوغرافية
العنوان: Discovery of a Novel Series of Potent, Selective, Orally Available, and Brain-Penetrable C1s Inhibitors for Modulation of the Complement Pathway.
المؤلفون: Ikeda Z; Research, Takeda Pharmaceutical Company Ltd., 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan., Kamei T; Research, Takeda Pharmaceutical Company Ltd., 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan., Sasaki Y; Research, Takeda Pharmaceutical Company Ltd., 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan., Reynolds M; Research, Takeda Pharmaceutical Company Ltd., 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan., Sakai N; Research, Takeda Pharmaceutical Company Ltd., 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan., Yoshikawa M; Research, Takeda Pharmaceutical Company Ltd., 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan., Tawada M; Research, Takeda Pharmaceutical Company Ltd., 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan., Morishita N; Research, Takeda Pharmaceutical Company Ltd., 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan., Dougan DR; Structural Biology, Takeda Development Center Americas, Inc., San Diego, California 92121, United States., Chen CH; Structural Biology, Takeda Development Center Americas, Inc., San Diego, California 92121, United States., Levin I; Structural Biology, Takeda Development Center Americas, Inc., San Diego, California 92121, United States., Zou H; Structural Biology, Takeda Development Center Americas, Inc., San Diego, California 92121, United States., Kuno M; Research, Takeda Pharmaceutical Company Ltd., 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan., Arimura N; Research, Takeda Pharmaceutical Company Ltd., 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan., Kikukawa Y; Research, Takeda Pharmaceutical Company Ltd., 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan., Kondo M; Discovery Biology, Discovery Science, Axcelead Drug Discovery Partners, Inc., 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-0012, Japan., Tohyama K; Research, Takeda Pharmaceutical Company Ltd., 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan., Sato K; Research, Takeda Pharmaceutical Company Ltd., 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
المصدر: Journal of medicinal chemistry [J Med Chem] 2023 May 11; Vol. 66 (9), pp. 6354-6371. Date of Electronic Publication: 2023 Apr 25.
نوع المنشور: Journal Article; Research Support, U.S. Gov't, Non-P.H.S.
اللغة: English
بيانات الدورية: Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE
أسماء مطبوعة: Publication: Washington Dc : American Chemical Society
Original Publication: [Easton, Pa.] : American Chemical Society, [c1963-
مواضيع طبية MeSH: Complement C1s*/chemistry , Complement C1s*/metabolism , Complement Activation*, Humans ; Serine Endopeptidases/metabolism ; Brain/metabolism
مستخلص: A novel series of non-amidine-based C1s inhibitors have been explored. Starting from high-throughput screening hit 3 , isoquinoline was replaced with 1-aminophthalazine to enhance C1s inhibitory activity while exhibiting good selectivity against other serine proteases. We first disclose a crystal structure of a complex of C1s and a small-molecule inhibitor ( 4e ), which guided structure-based optimization around the S2 and S3 sites to further enhance C1s inhibitory activity by over 300-fold. Improvement of membrane permeability by incorporation of fluorine at the 8-position of 1-aminophthalazine led to identification of ( R )-8 as a potent, selective, orally available, and brain-penetrable C1s inhibitor. ( R )-8 significantly inhibited membrane attack complex formation induced by human serum in a dose-dependent manner in an in vitro assay system, proving that selective C1s inhibition blocked the classical complement pathway effectively. As a result, ( R )-8 emerged as a valuable tool compound for both in vitro and in vivo assessment.
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المشرفين على المادة: EC 3.4.21.42 (Complement C1s)
EC 3.4.21.- (Serine Endopeptidases)
تواريخ الأحداث: Date Created: 20230430 Date Completed: 20230512 Latest Revision: 20230629
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC10184130
DOI: 10.1021/acs.jmedchem.3c00348
PMID: 37120845
قاعدة البيانات: MEDLINE
الوصف
تدمد:1520-4804
DOI:10.1021/acs.jmedchem.3c00348