MK-0952

Phosphodiesterase inhibitors (PDE-Is) enhance cAMP and/or cGMP signaling via reducing the degradation of these cyclic nucleotides. Since both cAMP and cGMP signaling are essential in a variety of cellular functions, including neuroplasticity and neuroprotection, PDE-Is are receiving increased attention as possible targets for treatment of age-related cognitive decline as well as Alzheimer's disease (AD). In this review we will give a translational overview of the preclinical and clinical data on PDE-Is and cognition enhancement focusing on aging and AD. PDE2, 4 and 5 inhibitors improved memory performance in both aged animals and models of AD. Treatment with a PDE3-I or PDE7-I has not been tested in aged animals yet, but in mouse models of AD both PDE-Is improved memory performance. Unfortunately, there are no peer-reviewed studies on the effects of PDE-I treatment in aged human subjects except the possible positive effect on memory impairment of the PDE1-I vinpocetine. Three other types of PDE-Is have been tested on cognition in mild to moderate AD patients: the PDE3-I cilostazol is being tested as a co-treatment to the acetylcholinesterase inhibitor donepezil, but with inconsistent results; the PDE4-I MK-0952 has been tested, although the outcome has not been disclosed yet; and the PDE9-I PF- 04447943 was reported to have no effects on cognition. Obviously, the demonstration of clinical proof of concept for cognition enhancing effects of PDE-Is and the generation of isoform selective PDE-Is are the final hurdles to overcome in developing safe and efficacious novel PDE-Is for the treatment of age-associated cognitive decline or AD.

The structure-activity relationship of a novel series of 8-biarylnaphthyridinones acting as type 4 phosphodiesterase (PDE4) inhibitors for the treatment of long-term memory loss and mild cognitive impairment is described herein. The manuscript describes a new paradigm for the development of PDE4 inhibitor targeting CNS indications. This effort led to the discovery of the clinical candidate MK-0952, an intrinsically potent inhibitor (IC(50)=0.6 nM) displaying limited whole blood activity (IC(50)=555 nM). Supporting in vivo results in two preclinical efficacy tests and one test assessing adverse effects are also reported. The comparative profiles of MK-0952 and two other Merck compounds are described to validate the proposed hypothesis.