Discovery of a Novel and Brain-Penetrant <i>O</i>-GlcNAcase Inhibitor via Virtual Screening, Structure-Based Analysis, and Rational Lead Optimization.

Tawada, Michiko; Fushimi, Makoto; Masuda, Kei; Sun, Huikai; Uchiyama, Noriko; Kosugi, Yohei; Lane, Weston; Tjhen, Richard; Endo, Satoshi; Koike, Tatsuki

Discovery of a Novel and Brain-Penetrant O-GlcNAcase Inhibitor via Virtual Screening, Structure-Based Analysis, and Rational Lead Optimization.

Tawada, Michiko; Fushimi, Makoto; Masuda, Kei; Sun, Huikai; Uchiyama, Noriko; Kosugi, Yohei; Lane, Weston; Tjhen, Richard; Endo, Satoshi; Koike, Tatsuki.

Affiliation

Tawada M; Research, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Fushimi M; Research, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Masuda K; Research, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Sun H; Takeda California, Inc., 9625 Towne Centre Drive, San Diego, California 92121, United States.
Uchiyama N; Research, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Kosugi Y; Research, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Lane W; Takeda California, Inc., 9625 Towne Centre Drive, San Diego, California 92121, United States.
Tjhen R; Takeda California, Inc., 9625 Towne Centre Drive, San Diego, California 92121, United States.
Endo S; Research, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Koike T; Research, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.

J Med Chem ; 64(2): 1103-1115, 2021 01 28.

Article in En | MEDLINE | ID: mdl-33404239

Subject(s)

Acetylglucosamine/antagonists & inhibitors; Enzyme Inhibitors/chemical synthesis; Enzyme Inhibitors/pharmacology; Neuroprotective Agents/chemical synthesis; Neuroprotective Agents/pharmacology; beta-N-Acetylhexosaminidases/antagonists & inhibitors; Animals; Brain/metabolism; Cell Line; Computer Simulation; Drug Design; Drug Evaluation, Preclinical; Enzyme Inhibitors/pharmacokinetics; Humans; Mice; Mice, Inbred C57BL; Models, Molecular; Molecular Docking Simulation; Molecular Dynamics Simulation; Neuroprotective Agents/pharmacokinetics; Structure-Activity Relationship; Tauopathies/drug therapy

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Full text: 1 Database: MEDLINE Main subject: Acetylglucosamine / Beta-N-Acetylhexosaminidases / Neuroprotective Agents / Enzyme Inhibitors Type of study: Diagnostic_studies / Prognostic_studies / Screening_studies Language: En Journal: J Med Chem Year: 2021 Type: Article Affiliation country: Japan

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