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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 2-arylpyrimidines with PDE4B inhibitory activity
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Figure 2: Analogues of 2-arylpyrimidines with PDE4B inhibitory activity

Mentions: In the year 2009, 2-arylpyrimidine derivative 4a (Figure 2) was identified as a selective and potent PDE4B inhibitor with an IC50 of sub-micromolar range (0.19 µM) and a potential 10-fold selectivity over PDE4D [38]. Authors further investigated the structure-activity relationship to optimize this lead compound which afforded a series of potent PDE4B inhibitors with >100-fold selectivity over the PDE4D isozyme. With a good pharmacokinetic profile, the selected compound exhibited potent anti-inflammatory properties. The compounds bearing allyl (4a), ethyl (4b), cyano (4c), or formyl (4d) groups at fifth position of the pyrimidine ring were found to be equipotent for PDE4B inhibition (pIC50190, 140, 120, and 300 nM, respectively) and 4B/4D selectivity. Bulkier groups at this position reduced the potency in derivatives 4f (PDE4B pIC50 1300 nM), 4g, 4h, and 4j (PDE4B pIC50>1000 nM in all three compounds). Derivative 4k, having an ethyl group at sixth position of the pyrimidine ring, showed enhanced potency (PDE4B pIC50 34 nM), but less selectivity compared with the methyl analog 4a. Authors also explored the SAR at second position of the pyrimidine ring. Potency and selectivity towards PDE4B was retained when the phenyl ring at second position of the pyrimidine ring was substituted with 2-thienyl 5a (Figure 2) (PDE4B pIC50 120 nM) or 3-thienyl 4b (PDE4B pIC50 68 nM) groups. However, substitution of thiazol-4-yl 5c (PDE4B pIC50 2800 nM), 2-pyridyl 5d (PDE4B pIC50 3700 nM), or pyradinyl 5e (PDE4B pIC50 860 nM) groups at the same position markedly reduced the potency. Similar results were observed when the phenyl ring was substituted at second position of the pyrimidine ring and a carboxymethyl group at fourth position of the aminophenyl moiety present at fourth position of the pyrimidine ring (6a) (Figure 2). However, compounds 6c and 6d, possessing a substituted thienyl group at R1 and a carboxymethyl group at second position of pyrimidine ring, showed more than a 25-fold selectivity towards PDE4B. Further modification of the above compounds resulted in compounds 7a–d (Figure 2), which showed potent inhibitory activity on PDE4B (pIC50 15 nM, 6.8 nM, and 15 nM, respectively) and >100-fold selectivity over PDE4D (PDE4B pIC50 1700 nM, 2900 nM, 3100 nM, respectively).


Selective Phosphodiesterase 4B Inhibitors: A Review.

Azam MA, Tripuraneni NS - Sci Pharm (2014)

Analogues of 2-arylpyrimidines with PDE4B inhibitory activity
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Analogues of 2-arylpyrimidines with PDE4B inhibitory activity
Mentions: In the year 2009, 2-arylpyrimidine derivative 4a (Figure 2) was identified as a selective and potent PDE4B inhibitor with an IC50 of sub-micromolar range (0.19 µM) and a potential 10-fold selectivity over PDE4D [38]. Authors further investigated the structure-activity relationship to optimize this lead compound which afforded a series of potent PDE4B inhibitors with >100-fold selectivity over the PDE4D isozyme. With a good pharmacokinetic profile, the selected compound exhibited potent anti-inflammatory properties. The compounds bearing allyl (4a), ethyl (4b), cyano (4c), or formyl (4d) groups at fifth position of the pyrimidine ring were found to be equipotent for PDE4B inhibition (pIC50190, 140, 120, and 300 nM, respectively) and 4B/4D selectivity. Bulkier groups at this position reduced the potency in derivatives 4f (PDE4B pIC50 1300 nM), 4g, 4h, and 4j (PDE4B pIC50>1000 nM in all three compounds). Derivative 4k, having an ethyl group at sixth position of the pyrimidine ring, showed enhanced potency (PDE4B pIC50 34 nM), but less selectivity compared with the methyl analog 4a. Authors also explored the SAR at second position of the pyrimidine ring. Potency and selectivity towards PDE4B was retained when the phenyl ring at second position of the pyrimidine ring was substituted with 2-thienyl 5a (Figure 2) (PDE4B pIC50 120 nM) or 3-thienyl 4b (PDE4B pIC50 68 nM) groups. However, substitution of thiazol-4-yl 5c (PDE4B pIC50 2800 nM), 2-pyridyl 5d (PDE4B pIC50 3700 nM), or pyradinyl 5e (PDE4B pIC50 860 nM) groups at the same position markedly reduced the potency. Similar results were observed when the phenyl ring was substituted at second position of the pyrimidine ring and a carboxymethyl group at fourth position of the aminophenyl moiety present at fourth position of the pyrimidine ring (6a) (Figure 2). However, compounds 6c and 6d, possessing a substituted thienyl group at R1 and a carboxymethyl group at second position of pyrimidine ring, showed more than a 25-fold selectivity towards PDE4B. Further modification of the above compounds resulted in compounds 7a–d (Figure 2), which showed potent inhibitory activity on PDE4B (pIC50 15 nM, 6.8 nM, and 15 nM, respectively) and >100-fold selectivity over PDE4D (PDE4B pIC50 1700 nM, 2900 nM, 3100 nM, respectively).

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