PDE4D: A Multipurpose Pharmacological Target

Abstract

Phosphodiesterase 4 (PDE4) enzymes catalyze cyclic adenosine monophosphate (cAMP) hydrolysis and are involved in a variety of physiological processes, including brain function, monocyte and macrophage activation, and neutrophil infiltration. Among different PDE4 isoforms, Phosphodiesterases 4D (PDE4Ds) play a fundamental role in cognitive, learning and memory consolidation processes and cancer development. Selective PDE4D inhibitors (PDE4Dis) could represent an innovative and valid therapeutic strategy for the treatment of various neurodegenerative diseases, such as Alzheimer's, Parkinson's, Huntington's, and Lou Gehrig's diseases, but also for stroke, traumatic brain and spinal cord injury, mild cognitive impairment, and all demyelinating diseases such as multiple sclerosis. In addition, small molecules able to block PDE4D isoforms have been recently studied for the treatment of specific cancer types, particularly hepatocellular carcinoma and breast cancer. This review overviews the PDE4DIsso far identified and provides useful information, from a medicinal chemistry point of view, for the development of a novel series of compounds with improved pharmacological properties.

Keywords: catechol moiety; drug design; neurodegenerative diseases; phosphodiesterases 4; phosphodiesterases 4D.

Figure 1

Superposition of Roflumilast (cyan, PDB code: 1XOQ) [18] and Rolipram (orange, PDB code: 1TBB) [23] crystallographic binding modes. The metal M, solvent S, and lipophilic Q1 and Q2 pockets are represented. Details on the coordination of Mg²⁺ and Zn²⁺ ions are reported.

Figure 2

Structure of different PDE4 subtypes.

Figure 3

Catechol-based PDE4DIs. The catechol portion is highlighted in red. Structural modifications of lead compounds LASSBio-448 and FCPE07 are reported in boxes.

Figure 4

General structure of the GEBR library (groups A, B, and C).

Figure 5

Molecular structure of catechol-based PDE4DIs GEBR-7b, GEBR-11b, GEBR-54, GEBR-32a, GEBR-18a, and GEBR-26g.

Figure 6

PDE4DIs with pyridine and pyrimidine scaffolds. The pyridine and pyrimidine portions are colored in blue. Structural modifications of lead compound 9 are reported in boxes.

Figure 7

Quinoline-based PDE4DIs. The quinoline portion is highlighted in green. The structural modification of lead compound 12 is reported in the box.

Figure 8

(A) Binding mode of compound 13 within PDE4D binding site (PDB code: 7CBJ) [157]. H-bonds are reported as red dotted lines. (B) Ligplot representation of receptor/ligand interactions.

Figure 9

PDE4DIs with pyridazinone and naphthyridine scaffolds. The pyridazinone and naphthyridine portions are colored orange. Structural modifications of lead compound NVP-ABE171 are reported in boxes.

Figure 10

Other heterocyclic PDE4DIs reported in the literature.

Figure 11

Natural PDE4DIs reported in the literature. The structural modifications of lead compounds Toddacoumalone and α-Mangostin are reported in boxes.

Figure 12

Schematic representation of the biological activities of different chemical scaffolds of reported PDE4DIs.