PF-06447475 is a highly potent, selective, brain penetrant LRRK2 inhibitor with IC0 of 3 nM/11 nM for Wt LRRK2/G2019S LRRK2 respectively. PF-06447475 was sufficiently potent in the LRRK2 whole cell assay (WCA; IC50=25 nM) (pS935 end point) to warrant additional profiling. Oral administration of PF-06447475 twice daily for 15 days was well tolerated at doses up to 60 mg kg-1 day-1 (31-fold Cave,0.24h; 70-fold Cmax) with only minimal alterations in RBC parameters, electrolytes, and food consumption without concurrent effects on body weight.
|Animal models||G2019S BAC-transgenic mice|
|Formulation||10% propylene glycol/20% PEG400/70% 9.5% methocellulose|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
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.
Henderson JL, et al. J Med Chem. 2015 Jan 8;58(1):419-32. PMID: 25353650.
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