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Selective Phosphodiesterase 4B Inhibitors: A Review.

Azam MA, Tripuraneni NS - Sci Pharm (2014)

Bottom Line: Phosphodiesterase 4B has constituted an interesting target for drug development.In recent years, a number of PDE4B inhibitors have been developed for their use as therapeutic agents.In this review, an up-to-date status of the inhibitors investigated for the inhibition of PDE4B has been given so that this rich source of structural information of presently known PDE4B inhibitors could be helpful in generating a selective and potent inhibitor of PDE4B.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Chemistry, J. S. S. College of Pharmacy, Ootacamund-643001, Tamil Nadu, India.

ABSTRACT
Phosphodiesterase 4B (PDE4B) is a member of the phosphodiesterase family of proteins that plays a critical role in regulating intracellular levels of cyclic adenosine monophosphate (cAMP) by controlling its rate of degradation. It has been demonstrated that this isoform is involved in the orchestra of events which includes inflammation, schizophrenia, cancers, chronic obstructive pulmonary disease, contractility of the myocardium, and psoriatic arthritis. Phosphodiesterase 4B has constituted an interesting target for drug development. In recent years, a number of PDE4B inhibitors have been developed for their use as therapeutic agents. In this review, an up-to-date status of the inhibitors investigated for the inhibition of PDE4B has been given so that this rich source of structural information of presently known PDE4B inhibitors could be helpful in generating a selective and potent inhibitor of PDE4B.

No MeSH data available.


Related in: MedlinePlus

Analogues of ethyl 4,5-disubstituted-4,5-dihydropyrazole-3-carboxylate with PDE4B inhibitory activity
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Figure 12: Analogues of ethyl 4,5-disubstituted-4,5-dihydropyrazole-3-carboxylate with PDE4B inhibitory activity

Mentions: Ethyl 4,5-disubstituted-4,5-dihydropyrazole-3-carboxylates 24–27 (Figure 12) were synthesized through Pd/C–Cu catalysis as a new class of PDE4B inhibitors [50]. Synthesized compounds were evaluated against the PDE4B enzyme isolated from Sf9 cells and results were compared with the reference compound rolipram, a well-known inhibitor of PDE4. All compounds showed significant inhibition (>70%) of PDE4B when tested at 30 µM. A dose-response study was also carried out using compound 27 which showed dose-dependent inhibition of PDE4B. It is well-known that inhibition of the PDE4D subtype is linked to the emetic response [51]; hence, compounds 24-27 were tested for their PDE4B selectivity over PDE4D. Tested compounds showed 20–30% inhibition at 30 µM indicating their approximately two-fold selectivity towards PDE4B. The in silico docking study result of compound 25 showed the interaction of the hydroxyl function of Tyr233 with pyrazole nitrogen, the π–π stacking interaction between the pyrazole ring and His234, coordinate interaction between the Mg+2 ion and the ester carbonyl function, and coordinate interaction between the Zn+2 ion and pyrazole nitrogen. On the other hand, the π–π stacking interaction between pyrazole and His234 and the coordinate interaction between Mg++ and the ester carbonyl group was observed in compound 26.


Selective Phosphodiesterase 4B Inhibitors: A Review.

Azam MA, Tripuraneni NS - Sci Pharm (2014)

Analogues of ethyl 4,5-disubstituted-4,5-dihydropyrazole-3-carboxylate with PDE4B inhibitory activity
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4318138&req=5

Figure 12: Analogues of ethyl 4,5-disubstituted-4,5-dihydropyrazole-3-carboxylate with PDE4B inhibitory activity
Mentions: Ethyl 4,5-disubstituted-4,5-dihydropyrazole-3-carboxylates 24–27 (Figure 12) were synthesized through Pd/C–Cu catalysis as a new class of PDE4B inhibitors [50]. Synthesized compounds were evaluated against the PDE4B enzyme isolated from Sf9 cells and results were compared with the reference compound rolipram, a well-known inhibitor of PDE4. All compounds showed significant inhibition (>70%) of PDE4B when tested at 30 µM. A dose-response study was also carried out using compound 27 which showed dose-dependent inhibition of PDE4B. It is well-known that inhibition of the PDE4D subtype is linked to the emetic response [51]; hence, compounds 24-27 were tested for their PDE4B selectivity over PDE4D. Tested compounds showed 20–30% inhibition at 30 µM indicating their approximately two-fold selectivity towards PDE4B. The in silico docking study result of compound 25 showed the interaction of the hydroxyl function of Tyr233 with pyrazole nitrogen, the π–π stacking interaction between the pyrazole ring and His234, coordinate interaction between the Mg+2 ion and the ester carbonyl function, and coordinate interaction between the Zn+2 ion and pyrazole nitrogen. On the other hand, the π–π stacking interaction between pyrazole and His234 and the coordinate interaction between Mg++ and the ester carbonyl group was observed in compound 26.

Bottom Line: Phosphodiesterase 4B has constituted an interesting target for drug development.In recent years, a number of PDE4B inhibitors have been developed for their use as therapeutic agents.In this review, an up-to-date status of the inhibitors investigated for the inhibition of PDE4B has been given so that this rich source of structural information of presently known PDE4B inhibitors could be helpful in generating a selective and potent inhibitor of PDE4B.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Chemistry, J. S. S. College of Pharmacy, Ootacamund-643001, Tamil Nadu, India.

ABSTRACT
Phosphodiesterase 4B (PDE4B) is a member of the phosphodiesterase family of proteins that plays a critical role in regulating intracellular levels of cyclic adenosine monophosphate (cAMP) by controlling its rate of degradation. It has been demonstrated that this isoform is involved in the orchestra of events which includes inflammation, schizophrenia, cancers, chronic obstructive pulmonary disease, contractility of the myocardium, and psoriatic arthritis. Phosphodiesterase 4B has constituted an interesting target for drug development. In recent years, a number of PDE4B inhibitors have been developed for their use as therapeutic agents. In this review, an up-to-date status of the inhibitors investigated for the inhibition of PDE4B has been given so that this rich source of structural information of presently known PDE4B inhibitors could be helpful in generating a selective and potent inhibitor of PDE4B.

No MeSH data available.


Related in: MedlinePlus