PF-06447475

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

PF-06447475 是一种高效、选择性、脑渗透性 LRRK2 激酶抑制剂，对于 WT LRRK2 和 G2019S 突变体的 IC50 分别为 3 和 11nM。

PF-06447475 is a highly potent, selective, brain penetrant LRRK2 kinase inhibitor with IC50 of 3 and 11nM for WT LRRK2 and G2019S mutant, respectively; PF-06447475 is also sufficiently potent in the LRRK2 whole cell assay with IC50 of 25 nM; protects nerve-like differentiated cells (NLCs) against rotenone induced noxious effect, prevents α-synuclein-induced neurodegeneration in rats.

PF-06447475 inhibits LRRK2 enzyme and LRRK2 in the whole cell assay with IC50s of 3 and 25 nM, respectively. Cells incubated with PF-06447475 alone (0.5, 1, 3 μM) or in the presence of ROT significantly reduces (S935)-LRRK2 kinase phosphorylation to control. PF-06447475 significantly preserves the nucleus morphology and ΔΨm of NLCs exposed to ROT compared to untreated and control. PF-475 significantly diminishes ROT-induced ROS generation to a similar extent to cells exposed to PF-475 alone.

In G2019S+ rats treated with PF-06447475, a significant reduction in microgliosis to levels found in wild-type rats could be observed. The proinflammatory marker MHC-II expressed on myeloid cells but not neurons also appears to be less abundant in confocal sections in G2019S+ rats treated with PF-06447475. PF-06447475 treatment in G2019S+ rats significantly lowers the number of CD68 cells recruited to the SNpc. PF-06447475 successfully blocks the enhanced neuroinflammation associated with G2019S-LRRK2 expression. Treatment of G2019S+ rats with PF-06447475 preserves TH expression in the dorsal striatum, consistent with drug attenuating neurodegeneration in the SNpc. PF-06447475 is well tolerated in rats.

PF06447475

Autophagy

LRRK2

G2019SLRRK2|LRRK2

Neurological Disease

——

1527473-33-1

305.3339

C17H15N5O

>98% (HPLC)

DMSO: ≥ 33 mg/mL

N#CC1=CC=CC(C2=CNC3=NC=NC(N4CCOCC4)=C32)=C1

Benzonitrile, 3-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-

(-20℃)

With Ice Pack

≥ 2 years