Parkinson’s disease (PD) is one of the most prevalent neurological diseases that affects over 6 million people across the world. Patients are often inflicted with a number of neurological effects that include “tremor at rest,” bradykinesia, impaired posture and balance, rigid muscles and loss of automatic movements. With current treatments having limited efficacy in treating these motor symptoms, there is an urgent unmet need to discover new therapies for PD. The inhibition of leucine-rich repeat kinase 2 (LRRK2) kinase activity has emerged as one of the most important, genetically supported strategies to slow or stop the progression of PD. Inspired by the emergence of macrocyclization in drug discovery, we invented a series of aminopyrimidine macrocycle LRRK2 inhibitors. We reasoned that stabilization of a bioactive conformation through macrocyclization could result in enhanced potency and selectivity while concealing polarity and minimizing molecular weight. We employed pre-synthesis design criteria (TPSA/EPSA (<u>&lt;</u>90/<u>&lt;</u>75), rP-gp, mBcrp BA:AB ≤ 4, rat MRT ≥ 1 h, HBD ≤ 2, FaSSIF solubility ≥ 50 μM) and structure-based drug design lessons learned from the aminoquinazoline series with promising brain penetrant properties. Our endeavors led to a potent macrocycle with excellent pharmacokinetic properties that was characterized as a clastogen and posed a DDI risk due to potent CYP3A4 induction. To address these challenges, we sought to strategically incorporate masked polarity through intramolecular hydrogen bonding and leverage 3-dimensionality in the proper vectors. We adapted our assay screening funnel to enable the identification of novel leads with mitigated genotoxicity and PXR risks. The design and synthesis efforts undertaken to develop an orthogonal risk profile to address safety risks and CNS penetration challenges that led to the discovery of a low dose and dose number CNS penetrant macrocyclic LRRK2i with mitigated genotoxicity and CYP induction risks will be discussed.

Discovery of potent, selective, CNS penetrant macrocyclic LRRK2 inhibitors for the treatment of Parkinson’s disease

Where thousands of chemistry professionals meet to share ideas and advance scientific and technical knowledge. Spring 2023 abstracts, posters, and presentations will launch at the end of March.

ACS Spring 2023

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.