Medicinal Chemistry

Design and discovery of novel LRRK2 inhibitors

Abstract

Robert K. Lesniak*, R. Jeremy Nichols, Marcus Schonemann, Jing Zhao, Chandresh R. Gajera, Grace Lam, Khanh C. Nguyen, Mark Smith and Thomas J. Montine

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. Increased Leucine Rich Repeat protein Kinase 2 (LRRK2) activity is hypothesized to cause PD in those who inherit GS-LRRK2, as well as other less common LRRK2 mutations, and possibly even contribute to the pathogenesis of sporadic PD in people without LRRK2 mutations. The clear advantage of these non-selective LRRK2 kinase inhibitors is their possible indication for all forms of PD. Unfortunately, multiple advanced compounds of this type of LRRK2 kinase inhibitor are accompanied by concerning untoward effects in lung and kidney (e.g., compounds developed by Genentech and Merck, GNE-7915 and MLi-2, respectively), calling into question the suitability of relatively non-selective LRRK2 kinase inhibitors for long-term treatment of older individuals. Furthermore, although these side-effects in lung and kidney have been reported to be reversible, the safety of long-term administration of such compounds is untested. 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.