2. Academic Validation
  3. First Optimization of Novel, Potent, Selective PDE11A4 Inhibitors for Age-Related Cognitive Decline

First Optimization of Novel, Potent, Selective PDE11A4 Inhibitors for Age-Related Cognitive Decline

  • J Med Chem. 2023 Oct 20. doi: 10.1021/acs.jmedchem.3c01088.
Shams Ul Mahmood 1 2,  Mariana Lozano Gonzalez 1 2,  Sreedhar Tummalapalli 1 2,  Jeremy Eberhard 3,  Judy Ly 3,  Charles S Hoffman 3,  Michy P Kelly 4,  John Gordon 5,  Dennis Colussi 5,  Wayne Childers 5,  David P Rotella 1 2
Affiliations

Affiliations

  • 1 Department of Chemistry & Biochemistry, Montclair State University, Montclair, New Jersey 07043, United States.
  • 2 Sokol Institute of Pharmaceutical Life Sciences, Montclair State University, Montclair, New Jersey 07043, United States.
  • 3 Biology Department, Boston College, Chestnut Hill, Massachusetts 02467, United States.
  • 4 Department of Anatomy & Neurobiology, School of Medicine, University of Maryland, Baltimore, Maryland 21201, United States.
  • 5 Moulder Center for Drug Discovery Research, Temple University, Philadelphia, Pennsylvania 19140, United States.
PMID: 37862143 DOI: 10.1021/acs.jmedchem.3c01088
Abstract

Phosphodiesterase 11A4 (PDE11A4) is a dual-acting cyclic nucleotide hydrolase expressed in neurons in the CA1, subiculum, amygdalostriatal transition area and amygdalohippocampal area of the extended hippocampal formation. PDE11A4 is the only PDE Enzyme to emanate solely from hippocampal formation, a key brain region for the formation of long-term memory. PDE11A4 expression increases in the hippocampal formation of both humans and rodents as they age. Interestingly, PDE11A knockout mice do not show age-related deficits in associative memory and show no gross histopathology. This suggests that inhibition of PDE11A4 might serve as a therapeutic option for age-related cognitive decline. A novel, yeast-based high throughput screen previously identified moderately potent, selective PDE11A4 inhibitors, and this work describes initial efforts that improved potency more than 10-fold and improved some pharmaceutical properties of one of these scaffolds, leading to selective, cell-penetrant PDE11A4 inhibitors, one of which is 10-fold more potent compared to tadalafil in cell-based activity.

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