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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

Structure of 2-phenylpyrimidine analogues showing selective PDE4B inhibitory activity
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Figure 16: Structure of 2-phenylpyrimidine analogues showing selective PDE4B inhibitory activity

Mentions: In a separate communication, 2-phenylpyrimidine 33 and 5-carbamoyl-2-phenylpyrimidine 34 derivatives (Figure 16) were reported as potent PDE4B (IC50 25 nM and 200 nM, respectively) and mTNF-α (IC50 390 and 690 nM, respectively) inhibitors [55]. Compounds were also evaluated in vivo against LPS-induced pulmonary neutrophilia in mice. In compound 34, substitution of methyl (35a) (PDE4B IC50 4000 nM) or methylthio (35b) (PDE4B IC50 2000 nM) groups (Figure 16) on sixth position of the pyrimidine ring markedly reduced the PDE4B inhibitory activity. Moreover, substitution of N-methylacetamide (36a) (PDE4B IC50 8200 nM), N,N-dimethylacetamide (36b) (PDE4B IC50 8% at 10 µM), and N-hydroxyacetamide (36c) (PDE4B IC50 42% at 3 µM) groups (Figure 16) on fifth position of the pyrimidine ring resulted in a marked decrease in potency, whereas derivative 37 (Figure 16) with the N-(2,2-dimethylpropyl)acetamide substituent on fourth position of the phenyl ring exhibited maximum in vitro inhibitory activities against PDE4B (IC50 8.3 nM) and TNF-α (IC50 3.0 nM). The 5-carbamoyl moiety of compound 37 exhibited a water-bridged hydrogen bonding network with Asn395 and Gln443 residues in an X-ray crystallography study. In derivatives 36a–c, substituents hindered these interactions and this may be the reason for the lowered potency. The higher potency of 37 is further supported by the lengthy neopentyl substituent which fits into the lipophilic pocket.


Selective Phosphodiesterase 4B Inhibitors: A Review.

Azam MA, Tripuraneni NS - Sci Pharm (2014)

Structure of 2-phenylpyrimidine analogues showing selective PDE4B inhibitory activity
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 16: Structure of 2-phenylpyrimidine analogues showing selective PDE4B inhibitory activity
Mentions: In a separate communication, 2-phenylpyrimidine 33 and 5-carbamoyl-2-phenylpyrimidine 34 derivatives (Figure 16) were reported as potent PDE4B (IC50 25 nM and 200 nM, respectively) and mTNF-α (IC50 390 and 690 nM, respectively) inhibitors [55]. Compounds were also evaluated in vivo against LPS-induced pulmonary neutrophilia in mice. In compound 34, substitution of methyl (35a) (PDE4B IC50 4000 nM) or methylthio (35b) (PDE4B IC50 2000 nM) groups (Figure 16) on sixth position of the pyrimidine ring markedly reduced the PDE4B inhibitory activity. Moreover, substitution of N-methylacetamide (36a) (PDE4B IC50 8200 nM), N,N-dimethylacetamide (36b) (PDE4B IC50 8% at 10 µM), and N-hydroxyacetamide (36c) (PDE4B IC50 42% at 3 µM) groups (Figure 16) on fifth position of the pyrimidine ring resulted in a marked decrease in potency, whereas derivative 37 (Figure 16) with the N-(2,2-dimethylpropyl)acetamide substituent on fourth position of the phenyl ring exhibited maximum in vitro inhibitory activities against PDE4B (IC50 8.3 nM) and TNF-α (IC50 3.0 nM). The 5-carbamoyl moiety of compound 37 exhibited a water-bridged hydrogen bonding network with Asn395 and Gln443 residues in an X-ray crystallography study. In derivatives 36a–c, substituents hindered these interactions and this may be the reason for the lowered potency. The higher potency of 37 is further supported by the lengthy neopentyl substituent which fits into the lipophilic pocket.

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