Discovery of MK-1468: A Potent, Kinome-Selective, Brain-Penetrant Amidoisoquinoline LRRK2 Inhibitor for the Potential Treatment of Parkinson’s Disease

Genetic mutation of the leucine-rich
repeat kinase 2
(LRRK2) protein
has been associated with Parkinson’s disease (PD), a disabling
and progressive neurodegenerative disorder that is devoid of efficacious
disease-modifying therapies. Herein, we describe the invention of
an amidoisoquinoline (IQ)-derived LRRK2 inhibitor lead chemical series.
Knowledge-, structure-, and property-based drug design in concert
with rigorous application of in silico calculations
and presynthesis predictions enabled the prioritization of molecules
with favorable CNS “drug-like” physicochemical properties.
This resulted in the discovery of compound 8, which was
profiled extensively before human ether-a-go-go (hERG) ion channel
inhibition halted its progression. Strategic reduction of lipophilicity
and basicity resulted in attenuation of hERG ion channel inhibition
while maintaining a favorable CNS efflux transporter profile. Further
structure- and property-based optimizations resulted in the discovery
of preclinical candidate MK-1468. This exquisitely selective
LRRK2 inhibitor has a projected human dose of 48 mg BID and a preclinical
safety profile that supported advancement toward GLP toxicology studies.