PF‐04447943

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

一种有效、选择性、脑渗透性、口服活性的 PDE9A 抑制剂，IC50 为 8.3 nM。

A potent, selective, brain penetrant, orally active PDE9A inhibitor with IC50 of 8.3 nM; displays high selectivity versus PDEs1-8 and 10-11 (>150-fold over PDE1C, IC50=1394 nM); significantly increases neurite outgrowth and synapse formation in cultured hippocampal neurons at 30-100 nM; enhances synaptic plasticity and cognitive function in rodents.Alzheimer's Disease Phase 2 Clinical.

Using recombinant human, rhesus, and rat PDE9A2 in a cell free assay Edelinontrine is shown to have a Ki of 2.8±0.26, 4.5±0.13, and 18.1±1.9 nM (n=4, 11 and 9 respectively). Edelinontrine is found to be highly selective over other PDE enzymes (PDE1, Ki=8600±2121 nM, n = 5; PDE2A3, Ki>99,000 nM; PDE3A, Ki>50,000 nM; PDE4A, Ki>29,000 nM; PDE5A, Ki=14,980±5025 nM, n=5; PDE6C, Ki=5324±2612 nM, n=4; PDE7A2, Ki>75,000 nM; PDE8A, Ki>50,000 nM; PDE10, Ki>51,250±20,056 nM, n=4; PDE11, Ki>80,000 nM) and no other significant activity at ~60 other receptors/enzymes. In HEK whole cells expressing rhesus PDE9A2, Edelinontrine inhibits ANP (0.3 μM) stimulated cGMP with an IC50 of 375±36.9 nM (n=16).

Based on i.v. and p.o. dosing, pharmacokinetic studies with Edelinontrine in the rat indicates a Tmax of 0.3 h, T1/2 of 4.9 h, Cl of 21.7 mL/min/kg and an oral bioavailability of 47%. Thirty minutes following oral administration in rats (1-30 mg/kg), Edelinontrine concentrations dose-dependently increase in blood, brain and cerebrospinal fluid (CSF). The brain:plasma exposure ratios 30 min after dosing range from 0.13 at the 1 mg/kg dose to 0.33 at the 30 mg/kg dose. CSF levels are approximately 50% of brain levels. In mice, Edelinontrine (3, 10, 30 mg/kg p.o.) dose-dependently increases plasma and brain concentrations of Edelinontrine while the brain to plasma ratio ranged from 0.26 to 0.7 although this is not entirely dose dependent. CSF cGMP levels increase in a dose-dependent manner from a basal level of 3 pmol/mL to 13.3 pmol/mL (3.5-fold) at the 30 mg/kg dose. CSF cGMP levels also increase in a dose-dependent manner from a basal level of 3 pmol/mL in vehicle treated animals to 13.3 pmol/mL (3.5-fold) at the 30 mg/kg dose. CSF cGMP levels are elevated at all doses tested with a maximal effect of 3.5 fold increase above controls at 30 mg/kg.

PF 04447943 | PF04447943 | PF-4447943

Angiogenesis

PDE

PDE

Neurological Disease

Alzheimer Disease

1082744-20-4

395.47

C20H25N7O2

>98% (HPLC)

DMSO : ≥ 54.6 mg/mL 138.07 mM

CC1CN(CC1C2=NC3=C(C=NN3C4CCOCC4)C(=O)N2)CC5=NC=CC=N5

6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

(-20℃)

With Ice Pack

≥ 2 years