Targeting Phosphodiesterases in the CNS

Kehler, Jan

doi:10.1016/b978-0-12-409547-2.12445-x

Cited by 2 publications

(3 citation statements)

References 98 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Found: C,56.31;H,6.11;N,-β-D-erythro-pentofuranosyl]-4methoxy-1H-pyrazolo [3,4-d]pyrimidine (2l), -α-D-erythro-pentofuranosyl]-4-methoxy-1H-pyrazolo- [3,4-d] pyrimidine (2ll), and 2-[2-Deoxy -3,5-di-O-(p-toluoyl)-β-Derythro-pentofuranosyl]-4-methoxy-2H-pyrazolo [3,4-d]pyrimidine (3l). Prepared from 4-methoxy-1H-pyrazolo [3,4-d]pyrimidine (1b) and 2-deoxy-3,5-di-O-(p-toluoyl)-α-D-erythro-pentofuranosyl chloride (7) (388 mg, 1.0 mmol) as described in General Method 1. THF conditions: 20 °C/4 h. DMSO conditions: 20 °C/1 h. Purification, from THF reaction: (the first chromatography system, FCC, SiO 2 , 10−80% EtOAc in heptane).…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

“…Many drug discovery efforts toward purine-recognizing targets involve creative mimicking of the endogenous purine core. This is the case for kinases, purine receptors, phosphodiesterases, and other important biological targets. Additionally, it has been observed that incorporation of an N atom to replace an aromatic CH group may provide substantial gains in potency and physical chemical properties in drug discovery lead compounds .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Solvent-Controlled, Site-Selective N-Alkylation Reactions of Azolo-Fused Ring Heterocycles at N1-, N2-, and N3-Positions, Including Pyrazolo[3,4-d]pyrimidines, Purines, [1,2,3]Triazolo[4,5]pyridines, and Related Deaza-Compounds

et al. 2018

View full text Add to dashboard Cite

Alkylation of 4-methoxy-1 H-pyrazolo[3,4- d]pyrimidine (1b) with iodomethane in THF using NaHMDS as base selectively provided N2-methyl product 4-methoxy-2-methyl-2 H-pyrazolo[3,4- d]pyrimidine (3b) in an 8/1 ratio over N1-methyl product (2b). Interestingly, conducting the reaction in DMSO reversed selectivity to provide a 4/1 ratio of N1/N2 methylated products. Crystal structures of product 3b with N1 and N7 coordinated to sodium indicated a potential role for the latter reinforcing the N2-selectivity. Limits of selectivity were tested with 26 heterocycles which revealed that N7 was a controlling element directing alkylations to favor N2 for pyrazolo- and N3 for imidazo- and triazolo-fused ring heterocycles when conducted in THF. Use of H-detected pulsed field gradient-stimulated echo (PFG-STE) NMR defined the molecular weights of ionic reactive complexes. This data and DFT charge distribution calculations suggest close ion pairs (CIPs) or tight ion pairs (TIPs) control alkylation selectivity in THF and solvent-separated ion pairs (SIPs) are the reactive species in DMSO.

show abstract

Section: ■ Experimental Sectionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Solvent-Controlled, Site-Selective N-Alkylation Reactions of Azolo-Fused Ring Heterocycles at N1-, N2-, and N3-Positions, Including Pyrazolo[3,4-d]pyrimidines, Purines, [1,2,3]Triazolo[4,5]pyridines, and Related Deaza-Compounds

et al. 2018

View full text Add to dashboard Cite

show abstract

“…The dual substrate enzyme PDE2A is highly expressed in some brain areas, such as nucleus accumbens, cortex, hippocampus [7], striatum, amygdala [12], substantia nigra, and olfactory neurons [13,14,15], thus being involved in complex neuronal processes like learning, concentration, memory, emotion, and related diseases [8,9]. 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 [8].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and In Vitro Evaluation of 8-Pyridinyl-Substituted Benzo[e]imidazo[2,1-c][1,2,4]triazines as Phosphodiesterase 2A Inhibitors

et al. 2019

View full text Add to dashboard Cite

Phosphodiesterase 2A (PDE2A) is highly expressed in distinct areas of the brain, which are known to be related to neuropsychiatric diseases. 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. 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. 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. BIT1 demonstrated much higher inhibition than other BIT derivatives (82.9% inhibition of PDE2A at 10 nM). BIT1 displayed an IC50 for PDE2A of 3.33 nM with 16-fold selectivity over PDE10A. 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. In vitro studies of BIT1 using mouse liver microsomes (MLM) disclosed BIT1 as a suitable ligand for 18F-labeling. Nevertheless, future in vivo metabolism studies are required.

show abstract

Targeting Phosphodiesterases in the CNS

Cited by 2 publications

References 98 publications

Solvent-Controlled, Site-Selective N-Alkylation Reactions of Azolo-Fused Ring Heterocycles at N1-, N2-, and N3-Positions, Including Pyrazolo[3,4-d]pyrimidines, Purines, [1,2,3]Triazolo[4,5]pyridines, and Related Deaza-Compounds

Solvent-Controlled, Site-Selective N-Alkylation Reactions of Azolo-Fused Ring Heterocycles at N1-, N2-, and N3-Positions, Including Pyrazolo[3,4-d]pyrimidines, Purines, [1,2,3]Triazolo[4,5]pyridines, and Related Deaza-Compounds

Synthesis and In Vitro Evaluation of 8-Pyridinyl-Substituted Benzo[e]imidazo[2,1-c][1,2,4]triazines as Phosphodiesterase 2A Inhibitors

Contact Info

Product

Resources

About