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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 pyrazolo[1,5-a]pyridine with PDE4B inhibitory activity
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Figure 8: Analogues of pyrazolo[1,5-a]pyridine with PDE4B inhibitory activity

Mentions: Further investigation established a basis for the development of potent PDE4-selective and dual PDE3/4-selective inhibitors [44]. In a separate communication [45] authors disclosed (−)-6-[7-methoxy-2-(trifluoromethyl)pyrazolo[1,5-a]pyridin-4-yl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone (18) (Figure 8) as a dual PDE3/4 inhibitor (PDE4B IC50 0.47) with potent bronchodilatory and anti-inflammatory activities and an improved therapeutic window over roflumilast in a number of in vitro and in vivo models used for pharmacological profiling. Based on the structure of compound 18 and in continuation of the above work, authors [46] disclosed a novel series of 4,4-dimethylpyrazolones 19a-h (Figure 8) as dual PDE3/4 inhibitors. Potential bicyclic heteroaromatic replacement subunits for the pyrazolo[1,5-a]pyridine core of this series has also been undertaken and the activity of the resulting compounds is described. Synthesized compounds were evaluated to optimize the effect of substituents on seventh position of the pyrazolo[1,5-a]-pyridine nucleus. Compounds 19a-h showed promising in vitro PDE4B inhibition (IC50 0.16, 0.017 µM, 0.41 µM, 0.079 µM, 0.015 µM, 0.035 µM, 0.0034 µM, 0.0075 µM, respectively). Interestingly, the 7-ethyl derivative (19b) was found to be 25-fold more effective as a PDE4 inhibitor than the 7-methoxy analog (19c), revealing that strict catechol ether is not required and indeed potentially detrimental to PDE4-inhibitory activity.


Selective Phosphodiesterase 4B Inhibitors: A Review.

Azam MA, Tripuraneni NS - Sci Pharm (2014)

Analogues of pyrazolo[1,5-a]pyridine with PDE4B inhibitory activity
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 8: Analogues of pyrazolo[1,5-a]pyridine with PDE4B inhibitory activity
Mentions: Further investigation established a basis for the development of potent PDE4-selective and dual PDE3/4-selective inhibitors [44]. In a separate communication [45] authors disclosed (−)-6-[7-methoxy-2-(trifluoromethyl)pyrazolo[1,5-a]pyridin-4-yl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone (18) (Figure 8) as a dual PDE3/4 inhibitor (PDE4B IC50 0.47) with potent bronchodilatory and anti-inflammatory activities and an improved therapeutic window over roflumilast in a number of in vitro and in vivo models used for pharmacological profiling. Based on the structure of compound 18 and in continuation of the above work, authors [46] disclosed a novel series of 4,4-dimethylpyrazolones 19a-h (Figure 8) as dual PDE3/4 inhibitors. Potential bicyclic heteroaromatic replacement subunits for the pyrazolo[1,5-a]pyridine core of this series has also been undertaken and the activity of the resulting compounds is described. Synthesized compounds were evaluated to optimize the effect of substituents on seventh position of the pyrazolo[1,5-a]-pyridine nucleus. Compounds 19a-h showed promising in vitro PDE4B inhibition (IC50 0.16, 0.017 µM, 0.41 µM, 0.079 µM, 0.015 µM, 0.035 µM, 0.0034 µM, 0.0075 µM, respectively). Interestingly, the 7-ethyl derivative (19b) was found to be 25-fold more effective as a PDE4 inhibitor than the 7-methoxy analog (19c), revealing that strict catechol ether is not required and indeed potentially detrimental to PDE4-inhibitory activity.

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