New Selective Phosphodiesterase 4D Inhibitors Differently Acting on Long, Short, and Supershort Isoforms

Abstract

The lack of selective inhibitors toward the long, short, or supershort phosphodiesterases (PDE4s) prevented researchers from carefully defining the connection between different enzyme isoforms, their brain localization, and their role in neurodegenerative diseases such as Alzheimer's disease (AD). In the search for new therapeutic agents for treating memory and learning disorders, we synthesized new rolipram related PDE4 inhibitors, which had some selectivity toward the long form PDE4D3. The first series was synthesized as racemate and then resolved by semipreparative HPLC on chiral supports. Herein we report the synthetic pathways to obtain compounds 1a-c, 2a-c, 3a-c, 4a-f, 5a,b, 6a,b, 7a,b, the chiral analytical study to resolve compounds 1a-c, 2a-c, 3a-c, the molecular docking study for compound 1c, and the biological results and some SAR considerations that provide some insights and hints for the structural requirements for PDE4D subtype selectivity and enzyme inhibition.

Memory-enhancing effects of GEBR-32a, a new PDE4D inhibitor holding promise for the treatment of Alzheimer’s disease

“…In this context, our group has recently synthesized and characterized several selective PDE4D full inhibitors, some of which showed cognitive-enhancing properties in rodents at doses that were devoid of emetic-like effects252627282930.…”

A Nonhuman Primate PET Study: Measurement of Brain PDE4 Occupancy by Roflumilast Using (R)-[11C]Rolipram

“…(R)-[ 11 C]rolipram rat PET study that the brain uptake of (R)-[ 11 C]rolipram was almost completely blocked by cold rolipram [27]. Considering non-PDE4 subtype selectivity of both rolipram and roflumilast [24,28], full blocking of (R)- [19], and there was possible change of fp after roflumilast administration. The relationship between the roflumilast and the PDE4 occupancy was weaker when V T / fp was used to calculate the target occupancy than V T was used as shown in Fig.…”

“…Rolipram binds nonselectively to all PDE4 subtypes (Bruno et al, 2009). As the subtypes differ with respect to their regulatory behavior and tissue expression patterns, PET radioligands with more selective to the subtypes of PDE4 would help to understand the function of PDE4 subtypes in future.…”

Synthesis, biological activities and pharmacokinetic properties of new fluorinated derivatives of selective PDE4D inhibitors

“…16 Our research on PDE4Is led to several series of small molecules structurally related to rolipram and characterized by good and selective PDE4D inhibition. [17][18][19] Among them, compound GEBR7b (7b, Fig. 1) increased memory performances in the object location test (OLT) and the object recognition test (ORT) in rodents, 13 and improved spatial memory in the APPswe/PS1dE9 mouse model of Alzheimer's disease (AD).…”

“…All compounds were tested in duplicate at the concentration of 10 lM, as previously reported. 18 We subsequently assessed their inhibitory potency on PDE4D3 (IC 50 values) and their selectivity compared with PDE4A4, PDE4B2, and PDE4C2 isoforms.…”