PDE2 (phosphodiesterase 2) is one of 21 different PDEs in mammals. Specifically, PDE has different substrate specificity. Some of them are cAMP selective hydrolases, others are cGMP selective hydrolases, others can hydrolyze cAMP and cGMP. In the central nervous system (CNS), both cAMP and cGMP play an important role in regulating intracellular signal transduction pathways associated with long-term potentiation (LTP). Besides, PDEs is an enzyme that degrades cyclic nucleotides in cells. There is only one gene family encoding PDE2, PDE2A. Moreover, it has three splicing variants, PDE2A1, PDE2A2, and PDE2A3.

PDE2A is a double substrate enzyme, which can hydrolyze camp and cGMP. Furthermore, PDE2A is highly expressed in the forebrain. And it is one of the key phosphor di esterases for the hydrolysis of camp and cGMP. Meanwhile, PDE2A can improve the cognitive impairment of schizophrenia or Alzheimer’s disease by up-regulating cyclic nucleotides in the brain. Thus it enhances the role of the cyclic nucleotide signaling pathway. Nonetheless, PDE2A inhibition is expected to improve cognitive impairment associated with aging. Here, we will introduce a selective, brain-penetrant, and orally active PDE2A inhibitor, TAK-915.

TAK-915 is a Selective, Brain-Penetrant, and Orally Active PDE2A Inhibitor.

To begin with, TAK-915 is a potent PDE2A inhibitor with an IC₅₀ of 0.61 nM. TAK-915 is >4100-fold more selectivity for PDE2A than PDE1A. Particularly, TAK-915 has the potential for neuropsychiatric and neurodegenerative disorders treatment.

Secondly, TAK-915 with 3 mg/kg/day by oral for 4 days significantly reduces escape latency in aged male F344 rats in the Morris water maze task. Importantly, TAK-915 dose-dependently attenuates the non-selective muscarinic antagonist scopolamine-induced memory deficits in rats.

Thirdly, oral dosing of TAK-915 in mice produces a dose-dependent increase in 3′,5′-cyclic guanosine monophosphate (cGMP) levels. Obviously, it has significant cGMP increases observed at a dose of 10 mg/kg.

Finally, TAK-915 improves cognitive deficits in several cognitive domains, including episodic and working memory rat models of schizophrenia. In particular, TAK-915 upregulates the phosphorylation of AMPA receptor subunitGluR1.

References:

Nakashima M, et al. Behav Brain Res. 2019 Dec 30;376:112192.