Chapter Four - Development of LRRK2 Kinase Inhibitors for Parkinson's Disease

• Autores: Paul Galatsis, Jaclyn Henderson, Bethany L. Kormos, Warren D. Hirst
• Localización: Annual reports in medicinal chemistry, ISSN 0065-7743, Vol 49, 2014, págs. 43-58
• Idioma: inglés
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• Resumen

  • Abstract Parkinson's disease (PD) is the most common movement disorder and the second most common neurodegenerative disorder after Alzheimer's disease. The etiology of PD is complex but the most common phenotype is the loss of dopaminergic neurons of the substantia nigra leading to the clinical symptoms of bradykinesia, resting tremors, rigidity, and postural instability. The most common genetic cause of autosomal dominant PD is mutations in leucine-rich repeat kinase 2 (LRRK2) which accounts for 1% of sporadic and 4% of familial cases. The G2019S mutation is the most common in LRRK2 and occurs in the DYG motif of the kinase domain, where it appears to increase its kinase activity. Consequently, a great deal of effort has been directed toward identifying potent LRRK2 kinase inhibitors with a biopharmaceutical profile congruent with clinical evaluation and this report summarizes efforts in this regard.