Detalle de: O5–06–03: Enhancing brain cAMP trough PDE‐7 inhibitors: A new Alzheimer's disease pharmacotherapy approach

The urgent need for effective drugs that address AD pathology leads us to investigate innovative drugs with new mechanism of action. Our working hypothesis is that a small molecule able to increase cAMP in brain will be able to correct AD pathology because: 1) trough CREB signaling, cAMP is involved in neuronal plasticity, so it may correct the cognition impairment and memory deficits; 2) cAMP is involved in neuroinflamation, decreasing gliosis and asctrocytosis and therefore levels of beta-amyloid and neuronal death; and finally 3) as cAMP activates PKA, through PKB cascade, may lead to the inactivation of GSK-3 decreasing also tau phosphorylation. Phosphodiesterase 7 (PDE7) is expressed in brain and its inhibitors could play a central role in AD recovering the homeostasis of cAMP. Candidate selection of a drug-like PDE7 inhibitor through lead-to-candidate programs designed to include in vivo pharmacokinetic profile and panel receptors profiling. Efficacy evaluation of the selected candidate on APPxPS1 mouse model after chronic treatment using different cognitive tests and inmunohistochemical techniques. Study of neuronal plasticity by spines analysis using microanatomical/computational tools. Our PDE-7 inhibitor, the quinoline compound called S14, has been selected as drug candidate with clean off-target bindings, good blood-brain penetration and oral bioavailability. Enhancement of brain cAMP using the small molecule S14 in APPxPS1 AD- mouse model is able to reverse pathological phenotype. Data shown that mice treated daily for 4 weeks with S14 have a significant attenuation in behavioral impairment, increase in neuron survival, low brain A b deposition and tau phosphorylation, and enhanced astrocyte-mediated A b degradation. These effects are mediated via cAMP/CREB signaling pathway and inactivation of GSK3. Changes in dendritic spines density and morphology in cortical pyramidal neurons should also contribute to this phenotype recovery. Results support the use of PDE7 inhibitors as effective drugs for the future AD-therapy. Specifically S14, merits to be developed to enter in clinical trials as disease-modifying drug for AD.