GNE-7915 is a moderately potent 5-HT2B antagonist. GNE-7915 demonstrates excellent in vitro DMPK with minimal turnover in human hepatocytes. GNE-7915 demonstrates excellent in vivo PK profiles with long half-lives, good oral exposure and high passive permeability.
|Animal models||BAC transgenic mice expressing human LRRK2 protein with the G2019S Parkinson’s disease mutation|
|Formulation||Suspended in 1% microcrystalline cellulose|
|Administration||i.p. ; p.o.|
|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.
|Source||CNS Neurosci Ther (2017). Figure 2. GNE-7915|
|Cell Lines||WT mice|
|Concentrations||1 and 3 μM|
|Results||In contrast, GSK2578215A and GNE-7915 at all concentrations had no effect on DA release and recovery. Western blot confirmed the dose–response inhibition by the LRRK2 inhibitions|
Discovery of highly potent, selective, and brain-penetrable leucine-rich repeat kinase 2 (LRRK2) small molecule inhibitors.
Estrada AA, et al. J Med Chem. 2012 Nov 26;55(22):9416-33. PMID: 22985112.
|Related LRRK2 Products|
JH-II-127 is a highly selective LRRK2 inhibitor with an IC50 = 6.5 nM.
LRRK2-IN-1 is useful in treatment of Parkinson's disease.
GSK2578215A is a potent and selective LRRK2 kinase inhibitor with IC50 of 8.9 nM and 10.9 nM for LRRK2 (G2019S) and LRRK2 (WT), respectively.
PF-06447475 is a highly potent, selective, brain penetrant LRRK2 inhibitor with IC0 of 3 nM/11 nM for Wt LRRK2/G2019S LRRK2 respectively.
GNE-9605 is a highly potent, selective, and brain-penetrant LRRK2 inhibitor with IC50 of 19 nM.
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