Leucine-rich repeat kinase 2 inhibitors: a patent review (2014-present)

ABSTRACT

Introduction: Disease-modifying treatment for Parkinson’s disease (PD) to halt or revert the disease progression remains an unmet medical need. LRRK2 kinase activity is abnormally elevated in PD patients carrying LRRK2 mutations, with G2019S as the most frequent one. Small molecules to inhibit LRRK2 kinase activity might provide a potential disease-modifying strategy for PD.

Areas covered: This review provides an update of small molecule LRRK2 inhibitors in patents published from January 2014 to October 2019. The molecules are classified by their structural scaffolds.

Expert opinion: Despite the tremendous efforts to push small molecule LRRK2 inhibitors toward clinical trials, the overall progress is somewhat disappointing due to the challenges in compound optimization and the putative concern of target-related adverse effects. It is challenging to optimize multiple parameters including kinase selectivity, CNS penetration, and unbound fraction in brain simultaneously. In addition, the on-target effect of morphologic changes observed in lung/kidney in pre-clinical studies for several frontrunner ATP-competitive inhibitors prevented their further development. With this regard, non-ATP-competitive inhibitors may provide a different safety profile for development. DNL201 and DNL151 have entered early clinical trials to evaluate tolerability and target engagement biomarkers. This will pave the way for the development for future LRRK2 inhibitors.

KEYWORDS:

• Parkinson’s disease
• lrrk2
• g2019s
• kinase activity
• CNS penetration

Article highlights

• The current article provides a comprehensive review on the relevant patents published from January 2014 and October 2019 for small molecule LRRK2 inhibitors, categorized by compounds’ structural scaffolds.

• Four structurally distinct scaffolds including the pyrrolopyrimidine series, the aminopyrimidine series, the pyrimidinyl/pyridinyl-indazole series, and the macrocycle series as ATP-competitive LRRK2 inhibitors have been extensively investigated by pharmaceutical industry and academia during the past 5 years, and more than 43 patents have been published. The general structures and LRRK2 kinase activities reported in these patents are reviewed, and the developability profile such as kinase selectivity and brain penetration of lead compounds from these scaffolds are highlighted.

• LRRK2 inhibition has been a potential breakthrough treatment strategy for both PD patients carrying LRRK2 mutations and sporadic PD. Two major challenges slowing down the discovery and development of small molecule LRRK2 inhibitors for PD are discussed. To optimize compounds’ kinase selectivity, brain penetration, and unbound fraction at the same time for desired profile is challenging. On the other hand, the concern of the putative target-related adverse effects observed in pre-clinical studies has prevented several frontrunner molecules from further development. Expert opinion has been given.

• Two small molecule LRRK2 inhibitors have entered the early clinical trial recently, and positive phase 1a data for one of which have been disclosed. Progression of the frontrunner in the phase 1b trial in patients will provide critical information regarding to safety and efficacy for its further development, and for the discovery and development of future LRRK2 inhibitors.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.