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Discovery of G2019S-Selective Leucine Rich Repeat Protein Kinase 2 inhibitors with in vivo efficacy.
Lesniak, Robert K; Nichols, R Jeremy; Schonemann, Marcus; Zhao, Jing; Gajera, Chandresh R; Fitch, William L; Lam, Grace; Nguyen, Khanh C; Smith, Mark; Montine, Thomas J.
Afiliação
  • Lesniak RK; Medicinal Chemistry Knowledge Center, Stanford ChEM-H, Stanford University, Stanford CA, 94305, USA; Department of Pathology, 300 Pasteur Drive, Stanford University, Stanford, CA, 94305, USA.
  • Nichols RJ; Department of Pathology, 300 Pasteur Drive, Stanford University, Stanford, CA, 94305, USA.
  • Schonemann M; Department of Pathology, 300 Pasteur Drive, Stanford University, Stanford, CA, 94305, USA.
  • Zhao J; Department of Pathology, 300 Pasteur Drive, Stanford University, Stanford, CA, 94305, USA.
  • Gajera CR; Department of Pathology, 300 Pasteur Drive, Stanford University, Stanford, CA, 94305, USA.
  • Fitch WL; Departments of Medicine and Microbiology & Immunology, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
  • Lam G; Departments of Medicine and Microbiology & Immunology, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
  • Nguyen KC; Departments of Medicine and Microbiology & Immunology, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
  • Smith M; Medicinal Chemistry Knowledge Center, Stanford ChEM-H, Stanford University, Stanford CA, 94305, USA. Electronic address: mxsmith@stanford.edu.
  • Montine TJ; Department of Pathology, 300 Pasteur Drive, Stanford University, Stanford, CA, 94305, USA. Electronic address: tmontine@stanford.edu.
Eur J Med Chem ; 229: 114080, 2022 Feb 05.
Article em En | MEDLINE | ID: mdl-34992038
ABSTRACT
Mutations in the Leucine Rich Repeat Protein Kinase 2 gene (LRRK2) are the most common genetic causes of Parkinson's Disease (PD). The G2019S mutation is the most common inherited LRRK2 mutation, occurs in the kinase domain, and results in increased kinase activity. We report the discovery and development of compound 38, an indazole-based, G2019S-selective (>2000-fold vs. WT) LRRK2 inhibitor capable of entering rodent brain (Kp = 0.5) and selectively inhibiting G2019S-LRRK2. The compounds disclosed herein present a starting point for further development of brain penetrant G2019S selective inhibitors that hopefully reduce lung phenotype side-effects and pave the way to providing a precision medicine for people with PD who carry the G2019S mutation.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Doença de Parkinson / Fármacos Neuroprotetores / Inibidores de Proteínas Quinases / Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina / Indazóis Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2022 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Doença de Parkinson / Fármacos Neuroprotetores / Inibidores de Proteínas Quinases / Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina / Indazóis Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2022 Tipo de documento: Article