Selective Phosphodiesterase 4B Inhibitors: A Review

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.

Keywords: Antiproliferative activity; Chronic obstructive pulmonary disease; Cyclic adenosine monophosphate; PDE4B; Phosphodiesterases (PDE) enzymes; Selective PDE inhibitors.

Fig. 1.

Structure of various congeners of pyrazolopyridine with PDE4B inhibitory activity

Fig. 2.

Analogues of 2-arylpyrimidines with PDE4B inhibitory activity

Fig. 3.

Analogues of 3-aminocarboxy-4-anilinoquinoline with PDE4B inhibitory activity

Fig. 4.

Structures of various congeners of 1-benzothiophene-3-carboxamides with PDE4B inhibitory activity

Fig. 5.

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

Fig. 6.

Analogues of 1,2-dimethyl-1H-pyrrolo[2,3-d]pyridazine with PDE4B inhibitory activity

Fig. 7.

Analogues of 1-(arylmethylidyne)-1,2,3,4-tetrahydro-1λ⁵-quinoline with PDE4B inhibitory activity

Fig. 8.

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

Fig. 9.

Analogues of 3,5-disubstituted-1,2,4-oxadiazole with promising PDE4B2 inhibitory activity

Fig. 10.

Analogues of hexahydrophthalazinone that have shown promising PDE4B2 inhibitory activity

Fig. 11.

Formoterol–phthalazinone hybrids that have shown promising PDE4B2 inhibitory activity

Fig. 12.

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

Fig. 13.

Cyano pyridine derivatives with PDE4B inhibitory activity

Fig. 14.

1,3,4-oxadiazole and 1,2,4-oxadiazole containing 1-ethyl-1H-pyrazolo[3,4-b]-pyridines with PDE4B inhibitory activity

Fig. 15.

Structure of 7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine analogue, an orally active PDE4B-selective inhibitor

Fig. 16.

Structure of 2-phenylpyrimidine analogues showing selective PDE4B inhibitory activity

Fig. 17.

Structure of spirooxindole that showed promising PDE4B inhibitory activity

Fig. 18.

Structure of benzofuran analogues that showed promising PDE4B inhibitory activity

Fig. 19.

Novel series of imidazophenoxazine-4-sulfonamides that have shown promising PDE4B inhibitory activity

Fig. 20.

Novel series of N-alkylated pyridazinones that have shown selective PDE4B inhibitory activity

Fig. 21.

Structure of benzoxazinone derivatives that have shown potent PDE4B inhibitory activity

Fig. 22.

Structure of the 5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine analogue that has shown highly selective PDE4B inhibition

Fig. 23.

Structure of 1,2-dihydroquinolinemethanesulfonamide analogues that have shown potent PDE4B inhibition and anticancer activity

Fig. 24.

Structure of 1,2,4-triazole analogues that have PDE4B inhibition and anticancer activity

Fig. 25.

Structure of 1,4-dihydropyridine analogues that have Ca²⁺ channel blocking and