Document Type
Article
Publication Date
10-10-2024
Journal / Book Title
Journal of Medicinal Chemistry
Abstract
PDE11A4 is a target of interest for the treatment of age-related memory disorders. A previous report from our laboratories described an amide series of potent, selective PDE11A4 inhibitors that was metabolically unstable. Investigation of heterocyclic amide isosteres for the labile amide moiety revealed distinct structure-activity relationships and identified several compounds with potency comparable to the amide series. This manuscript describes the characterization of structure-activity and structure-property relationships in this set, leading to the identification of an orally bioavailable, brain-penetrant, selective and potent PDE11A4 inhibitor. Target engagement experiments demonstrated PDE11A4 inhibition in the hypothalamus of mice that was absent in PDE11A4 knock out animals.
DOI
10.1021/acs.jmedchem.4c01794
Montclair State University Digital Commons Citation
Mahmood, Shams ul; Eberhard, Jeremy; Hoffman, Charles S.; Colussi, Dennis; Gordon, John; Childers, Wayne; Amurrio, Elvis; Patel, Janvi; Kelly, Michy P.; and Rotella, David P., "First Demonstration of In Vivo PDE11A4 Target Engagement for Potential Treatment of Age-Related Memory Disorders" (2024). Department of Chemistry and Biochemistry Faculty Scholarship and Creative Works. 626.
https://digitalcommons.montclair.edu/chem-biochem-facpubs/626
Rights
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Published Citation
Mahmood, S. U., Eberhard, J., Hoffman, C. S., Colussi, D., Gordon, J., Childers, W., Amurrio, E., Patel, J., Kelly, M. P., & Rotella, D. P. (2024). First Demonstration of In Vivo PDE11A4 Target Engagement for Potential Treatment of Age-Related Memory Disorders. Journal of medicinal chemistry, 67(19), 17774–17784. https://doi.org/10.1021/acs.jmedchem.4c01794