#Nitro pdf professional v.5.3.1.8 series#
The triazine series comprises benzo- and pyridine-fused imidazotriazine derivatives, some of which are depicted in Figure 1 (Compounds I ( TA1), II, and III), along with their binding affinities. In 2010, Biotie Therapies and Wyeth claimed a series of 1,2,4-triazine- and pyrazine-containing tricyclic compounds exhibiting dual inhibition against both PDE2A and PDE10A as therapeutic targets. The finding of BAY 60-7550 triggered many pharmaceutical companies to discover potent PDE2A inhibitors for potential use in treating a variety of brain diseases. However, this compound shows a poor pharmacokinetic profile, as well as poor ability to cross the blood-brain barrier. BAY 60-7550 ( Figure 1), the first highly-selective PDE2A inhibitor, has been widely used to evaluate PDE2A activity. Up to now, there have been several PDE2A inhibitors reported. These results suggest the use of PDE2A inhibitors for treatment of neuropsychiatric diseases such as Alzheimer’s disease and schizophrenia.
The activity of PDE2A inhibitors related to cognitive improvement has been evaluated in animal models. The inhibition of PDE2A will increase the intracellular levels of cGMP and cAMP in PDE2A-abundant tissues and may result in improvement of neuroplasticity and memory function. The dual substrate enzyme PDE2A is highly expressed in some brain areas, such as nucleus accumbens, cortex, hippocampus, striatum, amygdala, substantia nigra, and olfactory neurons, thus being involved in complex neuronal processes like learning, concentration, memory, emotion, and related diseases. PDEs 4, 7, and 8 are cAMP-specific and PDEs 5, 6, and 9 cGMP-specific, and others (PDEs 1, 2, 3, 10, and 11) hydrolyze both substrates.
The 11 family members of PDEs are encoded by 21 genes and classified by their substrate specificity. cAMP and cGMP are involved in a great variety of cellular functions related to physiological and pathophysiological processes in brain and periphery. Nevertheless, future in vivo metabolism studies are required.Ĭyclic nucleotide Phosphodiesterases (PDEs) represent a class of enzymes catalyzing the hydrolysis of the intracellular second messengers, cyclic Adenosine Monophosphate (cAMP) and cyclic Guanosine Monophosphate (cGMP). In vitro studies of BIT1 using mouse liver microsomes (MLM) disclosed BIT1 as a suitable ligand for 18F-labeling. This finding revealed that a derivative bearing both a 2-fluoro-pyridin-4-yl and 2-chloro-5-methoxy-phenyl unit at the 8- and 1-position, respectively, appeared to be the most potent inhibitor. BIT1 displayed an IC 50 for PDE2A of 3.33 nM with 16-fold selectivity over PDE10A. BIT1 demonstrated much higher inhibition than other BIT derivatives (82.9% inhibition of PDE2A at 10 nM). BIT derivatives ( BIT1– 9) were obtained by a seven-step synthesis route, and their inhibitory potency towards PDE2A and selectivity over other PDEs were evaluated. A series of novel fluorinated PDE2A inhibitors on the basis of a Benzoimidazotriazine (BIT) scaffold was prepared leading to a prospective inhibitor for further development of a PDE2A PET imaging agent. The development of suitable PDE2A tracers for Positron Emission Tomography (PET) would permit the in vivo imaging of the PDE2A and evaluation of disease-mediated alterations of its expression. Phosphodiesterase 2A (PDE2A) is highly expressed in distinct areas of the brain, which are known to be related to neuropsychiatric diseases.
0 kommentar(er)
