12 Sep Enzyme Inhibitor Shows Promise in Treating Memory Deficits in Alzheimer’s

MedicalResearch.com Interview with:

Dr. O‘Donnell

James O’Donnell, PhD
Dean and professor
Pharmacy and Pharmaceutical Sciences
University at Buffalo School of Pharmacy

Ying Xu, MD, PhD
Research associate professor
University at Buffalo School of Pharmacy and Pharmaceutical Sciences

MedicalResearch.com: What is the background for this study?

Response: We have been studying cyclic nucleotide phosphodiesterase (PDE), an enzyme, for quite a while as a potential target for neuropsychiatric disease.  One aspect involves the effects of PDE inhibitors on memory.  This was prompted by our earlier finding that one form of the enzyme, PDE4, is in the NMDA receptor signaling pathway in neurons; this pathway has been implicated in memory. 

MedicalResearch.com: What are the main findings? 

Response: Through use of existing compounds and molecular approaches, we have found that the PDE4D subtype of the enzyme is of particular importance, making it of interest to develop PDE4D-selective inhibitors.  This led to the collaboration with Tetra Therapeutics (formerly Tetra Discovery), which was developing such inhibitors that acted via an allosteric mechanism (see the J Med Chem paper).  We carried out experiments using a transgenic mouse line that expressed the key human sequence that provided PDE4D selectivity.  This led to confirmation that increasing cyclic AMP signaling via PDE4D inhibition improved memory (see Neuropsychopharmacology paper).  These data were key for a subsequent clinical trial.  A follow-up study showed that inhibitor BPN14770 also was effective in an Alzheimer’s disease-related mouse model (see J Pharmacol Exp Ther paper).  

MedicalResearch.com: What should readers take away from your report? 

Response: The novel inhibitor has shown promise in preclinical tests for treating memory deficits resulting from Alzheimer’s disease and other neuropsychiatric illnesses.  

MedicalResearch.com: What recommendations do you have for future research as a result of this work? 

Response: The next step is completion of the Phase II trial which will examine efficacy.  Future preclinical work will focus on identifying the neuronal signaling pathways and molecules involved in the actions of BPN14770.  This could suggest additional therapeutic drug targets.

MedicalResearch.com: Is there anything else you would like to add? 

Response: This has been a productive collaboration between the University at Buffalo School of Pharmacy and Pharmaceutical Sciences and Tetra Therapeutics.

Citation:

Su-Ying Cui, Ming-Xin Yang, Yong-He Zhang, Victor Zheng, Han-Ting Zhang, Mark E. Gurney, Ying Xu, James M. O’Donnell. Protection from amyloid β peptide-induced memory, biochemical and morphological deficits by a phosphodiesterase-4D (PDE4D) allosteric inhibitor. Journal of Pharmacology and Experimental Therapeutics, 2019; jpet.119.259986 DOI: 10.1124/jpet.119.259986

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Last Updated on September 12, 2019 by Marie Benz MD FAAD