This technology is a series of selective phosphodiesterase 4 (PDE4) inhibitors for treating memory impairment in Alzheimer’s Disease (AD).
Unmet Need: Therapeutic for ameliorating memory loss associated with AD
There are currently only a limited number of drugs available to attenuate memory deficits in AD. These drugs offer limited efficacy and have severe side effects. Recent research suggests that phosphodiesterase (PDE) inhibitors, notably PDE4, may be a promising target for the treatment of a variety of cognitive deficits and, in particular, memory impairment. Rolipram (a well-known unselective PDE4 inhibitor) is able to reverse the beta-amyloid induced dysfunction to ameliorate cognitive deficits in mouse models. However, despite the potential clinical relevance, the therapeutic use of Rolipram is limited because of its major side effect of emesis. Currently, there are no selective PDE4 inhibitors available on the market.
The Technology: Selective inhibition of PDE4 with reduced side-effects
This technology identifies several compounds that are capable of selectively inhibiting PDE4 activity. These compounds are selective for the type D isoform of PDE4, which is expressed in the hippocampus and cortex and has been implicated in AD-related memory deficits. As a result, these compounds are able to improve cyclic adenosine monophosphate (cAMP) release in hippocampi without the side effects associated with unselective inhibition of PDE4. These compounds, therefore, offer a potent therapeutic strategy for preventing memory loss in AD.
This technology has been validated in vivo in rodent models of AD.
Applications:
- Therapeutic for memory loss in AD
- Therapeutic for brain cAMP deficiency
- Research tool for studying PDE4 function
- Research tool for studying cortical and hippocampal cAMP
Advantages:
- Effective at low doses
- Reduced side-effects
- Highly selective, yielding fewer off-target effects
Lead Inventor:
Ottavio Arancio, M.D. Ph.D.
Patent Information:
Patent Issued
Related Publications:
Ricciarelli R, Brullo C, Prickaerts J, Arancio O, Villa C, Rebosio C, Calcagno E, Balbi M, van Hagen BT, Argyrousi EK, Zhang H, Pronzato MA, Bruno O, Fedele E. “Memory-enhancing effects of GEBR-32a, a new PDE4D inhibitor holding promise for the treatment of Alzheimer’s disease” Sci Rep. 2017 Apr 12;7:46320.
Brullo C, Ricciarelli R, Prickaerts J, Arancio O, Massa M, Rotolo C, Romussi A, Rebosio C, Marengo B, Pronzato MA, van Hagen BTJ, van Goethem NP, D’Ursi P, Orro A, Milanesi L, Guariento S, Cichero E, Fossa P, Fedele E, Bruno O. “New insights into selective PDE4D inhibitors: 3-(Cyclopentyloxy)-4-methoxybenzaldehyde O-(2-(2,6-dimethylmorpholino)-2-oxoethyl) oxime (GEBR-7b) structural development and promising activities to restore memory impairment” Eur J Med Chem. 2016 Nov 29;124:82-102.
Gong B, Vitolo OV, Trinchese F, Liu S, Shelanski M, Arancio O. “Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment.” J Clin Invest. 2004 Dec; 114(11): 1624-34.
Tech Ventures Reference:
