Therapeutic phosphodiesterase type 5 (PDE5) inhibitors

This technology includes two chemical compounds that are phosphodiesterase type 5 (PDE5) inhibitors with a benzonaphthyridine derivative chemical scaffold that has not previously been used to treat Alzheimer’s disease or other conditions involving phosphodiesterase PDE5 function.

Unmet Need: Alzheimer’s disease (AD) treatment option to alter disease course

There is currently no cure for Alzheimer’s disease (AD) and current therapeutic options are limited, mainly targeting related symptoms rather than mediating disease progression. Phosphodiesterase (PDE) is an enzyme that breaks phosphodiester bonds and PDE type 5 (PDE5) is found in various tissue types, including the brain. Prior studies have shown that PDE5 inhibition in the brain can improve memory and synaptic plasticity in different AD mouse models. Most importantly, large population studies on people who have been administered PDE5 inhibitors, have shown lowered risk to start Alzheimer’s Disease. Although various PDE5 inhibitors are marketed to treat erectile dysfunction (ED), they are not useful for AD as they have low selectivity or are unable to penetrate the blood brain barrier. There are currently no available compounds or approaches to selectively target PDE5 as a treatment for AD or related conditions.

The Technology: Phosphodiesterase type 5 inhibitor for neurodegenerative disease treatment

This technology describes two phosphodiesterase type 5 (PDE5) inhibitors based on a benzonaphthyridine derivative chemical scaffold that has previously not been used for PDE5 inhibition. Compared to current PDE5 inhibitors, these compounds have improved selectivity and efficacy for PDE5 inhibition with an increase in penetrance across the blood brain barrier. Furthermore, these compounds can inhibit other PDE isozymes to further evaluate and assess the impact of PDE inhibition in the brain and the overall effect on memory, plasticity, and in treating conditions such as Alzheimer’s disease.

Applications:

• Treatment for Alzheimer’s disease and disease progression
• Treatment for other conditions involving phosphodiesterase (PDE) function
• Research tool for study of neurological diseases involving PDE function as well as phosphorylation of CREB, a transcription factor involved in learning and memory that is a PDE5 target
• Research tool for studying Alzheimer’s disease progression and synaptic plasticity

Advantages:

• Increased selectivity and efficacy for PDE5 inhibition
• Penetrance of blood brain barrier for treatment of Alzheimer’s disease and neurological conditions
• Compatible with inhibition of other PDE enzymes
• Provide platform to study PDE function in the brain specifically
• Inhibition of PDE5 at nanomolar concentration
• Validated approach for PDE5 inhibition with therapeutic impact in Alzheimer’s disease

Lead Inventor:

Ottavio Arancio, M.D.,Ph.D

Patent Information:

Patent Issued (US 11,851,427)

Related Publications:

• Hainsworth AH, Arancio O, Elahi FM, Isaacs JD, Cheng F. “PDE5 inhibitor drugs for use in dementia” Alzheimers Dement (NY). 2023 Sep 25;9(3):e12412

• Teich AF, Sakurai M, Patel M, Holman C, Saeed F, Fiorito J, Arancio O. “PDE5 exists in human neurons and is a viable therapeutic target for neurologic disease” J Alzheimers Dis. 2016;52(1):295-302.

• Zuccarello E, Zhang H, Acquarone E, Pham D, Staniszewski A, Deng SX, Landry DW, Arancio O, Fiorito J. “Optimizing metabolic stability of phosphodiesterase 5 inhibitors: discovery of a potent N-(pyridine-3-ylmethyl)quinoline derivative targeting synaptic plasticity” Bioorg Med Chem Lett. 2023 Aug 15:92:129409

• Puzzo D, Loreto C, Giunta S, Musumeci G, Frasca G, Podda MV, Arancio O, Palmeri A. “Effect of phosphodiesterase-5 inhibition on apoptosis and beta amyloid load in aged mice” Neurobiol Aging. 2014 Mar;35(3):520-31.

• Gulisano W, Tropea MR, Arancio O, Palmeri A, Puzzo D. “Sub-efficacious doses of phosphodiesterase 4 and 5 inhibitors improve memory in a mouse model of Alzheimer’s disease” Neuropharmacology. 2018 Aug;138:151-159.

• Fiorito J, Vendome J, Saeed F, Staniszewski A, Zhang H, Yan S, Deng SX, Arancio O, Landry DW. “Identification of a Novel 1,2,3,4-Tetrahydrobenzo[b][1,6]naphthyridine Analogue as a Potent Phosphodiesterase 5 Inhibitor with Improved Aqueous Solubility for the Treatment of Alzheimer’s Disease” J Med Chem. 2017 Nov 9;60(21):8858-8875.

• Puzzo D, Sapienza S, Arancio O, Palmeri A. “Role of phosphodiesterase 5 in synaptic plasticity and memory” Neuropsychiatr Dis Treat. 2008 Apr;4(2):371-87

• Fiorito J, Saeed F, Zhang H, Staniszewski A, Feng Y, Francis YI, Rao S, Thakkar DM, Deng SX, Landry DW, Arancio O. “Synthesis of quinoline derivatives: discovery of a potent and selective phosphodiesterase 5 inhibitor for the treatment of Alzheimer’s disease” Eur J Med Chem. 2013 Feb;60:285-94

• Puzzo D, Staniszewski A, Deng SX, Privitera L, Leznik E, Liu S, Zhang H, Feng Y, Palmeri A, Landry DW, Arancio O. “Phosphodiesterase 5 inhibition improves synaptic function, memory, and amyloid-beta load in an Alzheimer’s disease mouse model” J Neurosci. 2009 Jun 24;29(25):8075-86

Tech Ventures Reference:

• IR CU12089

• Licensing Contact: Jerry Kokoshka