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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 pyridazino[4,5-b]indolizine with PDE4B inhibitory activity
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Figure 5: Analogues of pyridazino[4,5-b]indolizine with PDE4B inhibitory activity

Mentions: In search of new compounds to treat inflammation, the pyridazino[4,5-b]indolizine analogue 12a (Figure 5) was found to possess a 23-fold selectivity for PDE4B (Ki 2.60 lM) over PDE4D [42]. In order to improve potency and selectivity, the substituted phenyl analogues 12b–g were prepared and comparable results were obtained from a cell-based adenylyl cyclase functional assay (PDE4B, IC50 13.2 µM; PDE4D, IC50 >100 µM). Interestingly, the fluorine-substituted analogue 12e was found to have high selectivity towards PDE4B compared to the derivative 12a. In N-acetyl piperazine analogue 13 (Figure 6), the electron-withdrawing substituent on the 3-position of benzene significantly increased the PDE4B inhibitory potency (PDE4B Ki 1.90 µM). 1,2-Dimethyl-1H-pyrrolo[2,3-d]pyridazine analogues 14a–d (Figure 6) were synthesized and evaluated for the selective affinity for PDE4B compared to PDE4D. Results revealed that -Cl and -Br substituents, respectively, at second and fourth position of the phenyl ring reduced the PDE4B affinity.


Selective Phosphodiesterase 4B Inhibitors: A Review.

Azam MA, Tripuraneni NS - Sci Pharm (2014)

Analogues of pyridazino[4,5-b]indolizine with PDE4B inhibitory activity
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Analogues of pyridazino[4,5-b]indolizine with PDE4B inhibitory activity
Mentions: In search of new compounds to treat inflammation, the pyridazino[4,5-b]indolizine analogue 12a (Figure 5) was found to possess a 23-fold selectivity for PDE4B (Ki 2.60 lM) over PDE4D [42]. In order to improve potency and selectivity, the substituted phenyl analogues 12b–g were prepared and comparable results were obtained from a cell-based adenylyl cyclase functional assay (PDE4B, IC50 13.2 µM; PDE4D, IC50 >100 µM). Interestingly, the fluorine-substituted analogue 12e was found to have high selectivity towards PDE4B compared to the derivative 12a. In N-acetyl piperazine analogue 13 (Figure 6), the electron-withdrawing substituent on the 3-position of benzene significantly increased the PDE4B inhibitory potency (PDE4B Ki 1.90 µM). 1,2-Dimethyl-1H-pyrrolo[2,3-d]pyridazine analogues 14a–d (Figure 6) were synthesized and evaluated for the selective affinity for PDE4B compared to PDE4D. Results revealed that -Cl and -Br substituents, respectively, at second and fourth position of the phenyl ring reduced the PDE4B affinity.

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