Dual functional cholinesterase and PDE4D inhibitors for the treatment of Alzheimer's disease: Design, synthesis and evaluation of tacrine-pyrazolo[3,4-b]pyridine hybrids.
Considering the importance of PDE4D inhibition and the modulation of biometals in Alzheimer's disease (AD) therapeutics, we have designed, synthesized and evaluated a series of new clioquinol-rolipram/roflumilast hybrids as multitarget-directed ligands for the treatment of AD.
This review discusses the role of PDE4 in the orchestration of cAMP response element binding signaling in AD and outlines the benefits of targeting PDE4D specifically.
Specific behavioural tests (object location and Y-maze continuous alternation tasks) demonstrate that this PDE4D inhibitor is able to enhance memory in AD transgenic mice and concomitantly rescues their hippocampal long-term potentiation deficit.