The discovery of disease-modifying therapies for Parkinson's disease represents a critical need in neurodegenerative medicine.  Genetic mutations in LRRK2 have been suggested as risk factors for the development of PD and some of these mutations have been linked to increased LRRK2 kinase activity and neuronal toxicity in cellular and animal models.  As such, research towards brain-permeable kinase inhibitors of LRRK2 has received much attention.  During our efforts to this end, a 5-azaindazole series was optimized for potency, metabolic stability and brain penetration.  A key design element involved the incorporation of an intramolecular hydrogen bond to increase permeability and potency against LRRK2.  This poster will outline the structure-activity relationships of a �matched pair� series including the challenge of obtaining a desirable balance between metabolic stability and brain penetration.

Development of potent azaindazole LRRK2 inhibitors with a key intramolecular hydrogen bond

245th National Meeting (2013)

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