Mutations in the kinase LRRK2 have been linked to autosomal dominant Parkinson’s Disease (PD) that is indistinguishable in clinical presentation to idiopathic PD. The pathogenic mutations segregate in the kinase and GTPase domains and have been demonstrated to result in increased kinase activity in vitro and in vivo. Furthermore, increased LRRK2 kinase activity has been observed in idiopathic PD. Taken together, inhibition of LRRK2 kinase activity represents a tractable, potentially disease modifying mechanism to treat PD. Over the last decade, there has been intense research into the development of high-quality brain-penetrant LRRK2 inhibitors. Indeed, the first inhibitors have entered clinical trials, and discovery efforts are aimed at achieving significant levels of target engagement in the brain while minimizing safety risks. Towards this goal we undertook the optimization of a series of N-heteroaryl indazole kinase inhibitors where we were faced with the challenge of reconciling kinase inhibitor property space with CNS druglike property space. A combination of structure-based drug design and parallel medicinal chemistry, enabled by nickel catalyzed sp³-sp² coupling technologies, led to the discovery of a series of indazolyl-spirocarbonitriles with improved properties. Lead compound MLi-0030 emerged from this series and was profiled extensively preclinically (Figure 1). MLi-0030 shows exceptional potency in human PBMCs, excellent kinase selectivity, good brain exposure in rodents, and has a low projected human dose. The full account of the discovery, optimization and preclinical profiling of MLi-0030 will be presented.

Joey Methot

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