Discovery and Preclinical Profiling of 3‑[4-(Morpholin-4-yl)‑7H‑pyrrolo[2,3‑d]pyrimidin-5-yl]benzonitrile
(PF-06447475), a Highly Potent, Selective, Brain Penetrant, and in
Vivo Active LRRK2 Kinase Inhibitor
posted on 2015-01-08, 00:00authored byJaclyn
L. Henderson, Bethany L. Kormos, Matthew M. Hayward, Karen J. Coffman, Jayasankar Jasti, Ravi G. Kurumbail, Travis T. Wager, Patrick R. Verhoest, G. Stephen Noell, Yi Chen, Elie Needle, Zdenek Berger, Stefanus J. Steyn, Christopher Houle, Warren D. Hirst, Paul Galatsis
Leucine
rich repeat kinase 2 (LRRK2) has been genetically linked
to Parkinson’s disease (PD) by genome-wide association studies
(GWAS). The most common LRRK2 mutation, G2019S, which is relatively
rare in the total population, gives rise to increased kinase activity.
As such, LRRK2 kinase inhibitors are potentially useful in the treatment
of PD. We herein disclose the discovery and optimization of a novel
series of potent LRRK2 inhibitors, focusing on improving kinome selectivity
using a surrogate crystallography approach. This resulted in the identification
of 14 (PF-06447475), a highly potent, brain penetrant
and selective LRRK2 inhibitor which has been further profiled in in
vivo safety and pharmacodynamic studies.