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

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

“…1). The 4-(difluoromethoxy)-3-hydroxybenzaldehyde, a key intermediate for GEBR-32a synthesis, was prepared using a novel microwave assisted procedure29 with improved yield with respect to other protocols reported in the literature.…”

“…We prepared the starting product 4-(difluoromethoxy)-3-hydroxybenzaldehyde ( 1 ) using our recently reported microwave assisted procedure with improved yield in comparison to many other procedures reported in the literature29. The 3-(cyclopentyloxy)-4-(difluoromethoxy)benzaldehyde ( 2 ) was then obtained by alkylation with bromocyclopentane in anhydrous N,N -dimethylformamide (DMF), in the presence of potassium carbonate and potassium iodide [A. Thomas et al .…”

“…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.…”

Metabolic and Pharmaceutical Aspects of Fluorinated Compounds

“…The use of OCHF 2 moieties to avert O-demethylation has been described in other studies. For example, this structural element is featured in several PDE4 inhibitors that have been explored for their anti-inflammatory effects against aberrant immune cells. − However, several of these compounds were eventually recognized to carry on-target liabilities that were exacerbated in some cases by high exposure . In light of these issues, intratracheal/intranasal administration of CHF 6001 ( 253 ) was explored as a treatment for inflammatory pulmonary disorders, and despite extensive metabolism of the compound in rats prior to disposition, the difluoromethoxy group of [ 14 C]- 253 remained intact in all metabolites identified in the urine and feces .…”

Pharmacodynamic assessment of apremilast for the treatment of moderate-to-severe plaque psoriasis

“…Supernatants from psoriatic NK cells have been shown to produce large amounts of IFN-γ, and to induce expression of ICAM-1 and MHC class II in psoriatic keratinocytes[59].Therapeutically, apremilast represent a promising option as it is well-tolerated and no blood test or imaging exam is mandatory during treatment. Another important advantage of apremilast is the route of administration and the possibility to be self-administered, the short half-life also makes apremilast convenient in case of sudden treatment interruption due, for example, to pregnancy or before major surgical intervention[60]. Nevertheless, no data o clinical reports are available regarding safety of apremilast during pregnancy and it is currently labeled as pregnancy category C drug.Because of the effectiveness in modulating the inflammatory cascade in adaptive and innate immune system and the pharmacokinetic advantages, apremilast may offers an oral treatment option for those patients who discontinue treatments because of ineffectiveness, intolerability, or ineligibility to the currently available drugs.According with the current armamentarium for the treatment of psoriasis and the efficacy profile, apremilast could be recommended for biologic-naïve patients and in subjects who are contraindicated for any conventional systemic or biologic therapy.…”